Cyclic amine compounds and pharmaceutical use

ABSTRACT

A cyclic amine compound is defined by the formula: ##STR1## in which J is indanyl, indanonyl, indenyl, indenonyl, indanedionyl, tetralonyl, benzosuberonyl, indanolyl or a divalent group thereof, K is phenyl, an arylalkyl or cynnamyl, B is --(CHR22) r--, R22 being H or methyl, --CO-- (CHR22)r--, ═(CH--CH═CH)b--, ═CH--(CH2)c-- or ═(CH--CH)d═ and the ring including T and Q is piperidine. The compound is useful to treat senile dementia.

This is a division of Ser. No. 07/209,339 now U.S. Pat. No. 4,895,841,filed June 20, 1988.

The invention relates to a cyclic amine compound, a therapeuticalcomposition and medical treatment of senile dementia.

STATEMENT OF PRIOR ARTS

With a rapid increase in the population of aged people, theestablishment of the therapy for senile dementia, such as Alzheimersenile dementia, is eagerly desired.

Various attempts have been made to treat the senile dementia with adrug. So far, however, there has been no drug which is very useful forthe treatment of these diseases.

Studies on the development of therapeutic agents for these diseases havebeen made from various aspects. Particularly, since Alzheimer seniledementia is accompanied by the lowering in cholinergic hypofunction, thedevelopment of the therapeutic agent from the aspect of an acetylcholineprecursor and an acetylcholinesterase inhibitor was proposed and has infact been attempted. Representative examples of the anticholinesteraseinhibitors include physostigmine and tetrahydroaminoacridine. However,these drugs have drawbacks such as an unsatisfactory effect and theoccurrence of unfavorable side effects. At the present time, there areno decisive therapeutic agents.

In view of the above situation, the present inventors have madeextensive and intensive studies on various compounds for many years witha view to developing a drug which has a persistent activity and a highsafety.

As a result, the present inventors have found that a piperidinederivative represented by the following general formula (I) can attainthe desired object.

Specifically, the compound of the present invention represented by thefollowing general formula (I) has great advantages of having strong andhighly selective antiacetylcholinesterase activity, increasing theamount of acetylcholine present in the brain, exhibiting an excellenteffect on a model with respect to disturbance of memory, and having apersistent activity and a high safety when compared with physostigminewhich is a conventional popular drug in the art, which renders thecompound of the present invention very valuable.

The compound of the present invention was found based on theacetylcholinesterase inhibitory action and, therefore, is effective fortreatment and prevention of various diseases which are thought to bederived from the deficiency of acetylcholine as a neurotransmitter invivo.

Examples of such diseases include various kinds of dementia includingAlzheimer senile dementia and further include Huntington's chorea,Pick's disease and ataxia.

Therefore, the objects of the present invention are to provide a novelpiperidine derivative effective as a pharmaceutical, particularly fortreatment and prevention of central nervous system diseases, to providea process for preparing the same, and to provide a pharmaceuticalcomprising the same as an effective ingredient.

SUMMARY OF THE INVENTION

The invention provides a cyclic amine compound having the followingformula (XXV) and a pharmacologically acceptable salt thereof: ##STR2##in which J is (a) a group, substituted or unsubstituted, selected fromthe group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4)quinolyl, (5) cyclohexyl, (6) quinoxalyl and (7) furyl;

(b) a monovalent or divalent group, in which the phenyl may have asubstituent(s), selected from the group consisting of (1) indanyl, (2)indanonyl, (3) indenyl, (4) indenonyl, (5) indanedionyl, (6) tetralonyl,(7) benzosuberonyl, (8) indanolyl and (9) C₆ H₅ --CO--CH(CH₃)--;

(c) a monovalent group derived from a cyclic amide compound;

(d) a lower alkyl or

(e) a group of R²¹ --CH═CH-- in which R²¹ is hydrogen or a loweralkoxycarbonyl;

B is --(CHR²²)_(r) --, --CO--(CHR²²)_(r) --, --NR⁴ --(CHR²²)_(r) --, R⁴being hydrogen, a lower alkyl, an acyl, a lower alkylsulfonyl, phenyl, asubstituted phenyl, benzyl or a substituted benzyl, --CO--NR⁵--(CHR²²)_(r) --, R⁵ being hydrogen, a lower alkyl or phenyl,--CH═CH--(CHR²²)_(r) --, --OCOO--(CHR²²)_(r) --, --OOC--NH--(CHR²²)_(r)--, --NH--CO--(CHR²²)_(r) --, --CH₂ --CO--NH--(CHR²²)_(r) --, --(CH₂)₂--CO--NH--(CHR²²)_(r) --, --CH(OH)--(CHR²²)_(r) --, r being zero or aninteger of 1 to 10, R22 being hydrogen or methyl so that one alkylenegroup may have no methyl branch or one or more methyl branch,═(CH--CH═CH)b--, b being an integer of 1 to 3, ═CH--(CH₂)_(c) --, cbeing zero or an integer of 1 to 9, ═(CH--CH)_(d) ═, d being zero or aninteger of 1 to 5; --CO--CH═CH--CH₂ --, --CO--CH₂ --CH(OH)--CH₂ --,--CH(CH₃)--CO--NH--CH₂ --, --CH═CH--CO--NH--(CH₂)₂ --, --NH--, --O--,--S--, a dialkylaminoalkylcarbonyl or a lower alkoxycarbonyl;

T is nitrogen or carbon;

Q is nitrogen, carbon or >N→O; and

q is an integer of 1 to 3;

K is hydrogen, phenyl, a substituted phenyl, an arylalkyl in which thephenyl may have a substituent, cinnamyl, a lower alkyl, pyridylmethyl, acycloalkylalkyl, adamantanemethyl, furylmethyl, a cycloalkyl, a loweralkoxycarbonyl or an acyl; and

shows a single bond or a double bond.

In the compounds having the formula (XXV), it is preferable that J is(a) or (b). In the definition (b), monovalent groups of (2), (3) and (5)and divalent groups of (2) are preferable, In the definition of B,--(CHR22)r--, ═(CH--CH═CH)b--, ═CH--(CH2)c-- and ═(CH--CH)d═ arepreferable. These preferable groups of (B) may be connected with (b) ofJ, in particular (2) of (b).

It is preferable in the formula (XXV) that Q is nitrogen, T is carbonand q is 1 or 3; and Q is carbon, T is nitrogen and q is 2. It is mostpreferable that Q is nitrogen, T is carbon and q is 2.

It is preferable that K is a phenylalkyl or a phenylalkyl having asubstituent(s) on the phenyl.

Preferable compounds of the invention include:

1-benzyl4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,

1-benzyl4-((5,6-dimethoxy-1-indanon)-2-ylidenyl)methylpiperidine,

1-benzyl4-((5-methoxy-1-indanon)-2-yl)methylpiperidine,

1-benzyl4-((5,6-diethoxy-1-indanon)-2-yl)methylpiperidine,

1-benzyl4-((5,6-methylenedioxy-1-indanon)-2-yl)methylpiperidine,

1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,

1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,

1(m-florobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,

1-benzyl4-((5,6-dimethoxy-1-indanon)-2-yl)propylpiperidine,

1-benzyl4-((5-isopropoxy-6-methoxy-1-indanon)-2-yl)methylpiperidine and

1-benzyl4-(5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine, havingthe below shown formula, shown in Example 224. ##STR3##

In addition, the invention provides a therapeutical composition whichcomprises a pharmacologically effective amount of the cyclic aminecompound having the formula (XXV) or a pharmacologically acceptable saltthereof and a pharmacologically acceptable carrier and then a method forpreventing and treating a disease due to the acetylcholinesteraseactivity by administering to a human patient the cyclic amine compoundhaving the formula (XXV) or a pharmacologically acceptable salt thereof.

The perferable compound has the above shown formula in which J is (b).The group (b) includes ten groups having the respective formulae shownbelow. S is hydrogen or a substituent such as a lower alkyl having 1 to6 carbon atoms and a lower alkoxy having 1 to 6 carbon atoms. Among thesubstituents, methoxy is most preferable. t is an integer of 1 to 4. Thephenyl is most preferred to have 1 to 3 methoxy groups thereon. (S)_(t)may form methylene dioxy group or ethylene dioxy group on two adjacentcarbon atoms of the phenyl group. ##STR4##

a preferable definition of B includes --(CHR²²)_(r) --,--CO--(CHR²²)_(r) --, ═(CH--CH═CH)_(b) --, ═CH--(CH₂)_(c) -- and═(CH--CH)_(d) ═. The group of (CHR²²)_(r) -- in which R²² is hydrogenand r is an integer of 1 to 3 and then the group of ═CH--(CH₂)_(c) --are most preferable.

In the above defined cyclic amine compound of the invention, it ispreferable that J in the formula is (b) the monovalent or divalentgroup. In the definition (b), indanonyl, indanedionyl and indenyl aremost preferable, optionally having a substituent(s) on the phenyl.

In the definition B, (CHR²²)_(r) -- and ═CH--(CH₂)_(c) -- arepreferable.

In the ring including T and Q, it may be a 5-, 6- or 7-membered ring. Itis preferable that Q is nitrogen, T is carbon or nitrogen and n is 2; Qis nitrogen, T is carbon and n is 1 or 3; and Q is carbon, T is nitrogenand n is 2.

In the definition K, phenyl, an arylalkyl and cinnamyl are preferable,optionally having a substituent(s) on the phenyl.

The invention will be explained in detail in view of the piperidinecompounds which fall within the scope of the above defined cyclic aminecompound. The explanation applies to the entire invention of the cyclicamine compound.

The piperidine compound is defined by the formula (I): ##STR5## whereinR¹ is the following substituted or unsubstituted group: 1 a phenylgroup, 2 a pyridyl group, 3 a pyrazyl group, 4 a quinolyl group, 5 anindanyl group, 6 a cyclohexyl group, 7 a quinoxalyl group, or 8 a furylgroup; a monovalent or divalent group derived from an indanone having anunsubstituted or substituted phenyl ring; a monovalent group derivedfrom a cyclic amide compound; a lower alkyl group or a group representedby the formula R³ --CH═C-- (wherein R³ is a hydrogen atom or a loweralkoxycarbonyl group),

X is a group represented by the formula --(CH₂)_(n) --, a grouprepresented by the formula ##STR6## a group represented by the formula##STR7## (wherein R⁴ is a hydrogen atom, a lower alkyl group, an acylgroup, a lower alkylsulfonyl group, or a substituted or unsubstitutedphenyl or benzyl group), a group represented by the formula ##STR8##(wherein R⁵ is a hydrogen atom, a lower alkyl group, or a phenyl group),a group represented by the formula --CH═CH--(CH₂)_(n) --, a grouprepresented by the formula ##STR9## a group represented by the formula##STR10## a group represented by the formula --CH═CH--CH═CO--, a grouprepresented by the formula ##STR11## a group represented by the formula##STR12## a group represented by the formula ##STR13## a grouprepresented by the formula ##STR14## a group represented by the formula##STR15## a group represented by the formula ##STR16## a grouprepresented by the formula ##STR17## a group represented by the formula##STR18## a dialkylaminoalkylcarbonyl group, or a lower alkoxycarbonylgroup, provided that n's in the above definition of X are eachindependently an integer of 0 to 6,

R² is a substituted or unsubstituted phenyl group, a substituted orunsubstituted arylalkyl group, a cinnamyl group, a lower alkyl group, apyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl group,or a furoylmethyl group,

and a symbol, , in the above general formula, means a single bond or adouble bond.

The term "lower alkyl group" used in the above definition of R¹, R², R⁴and R⁵ with respect to the compound (I) of the present invention isintended to mean a straight-chain or branched alkyl group having 1 to 6carbon atoms, and examples thereof include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl),isopenthyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl groups. Among them,methyl, ethyl, propyl, isopropyl groups etc. are preferable. A methylgroup is the most preferable.

Examples of the substitutent involved in the expression "the followingsubstituted or unsubstituted group: 1 a phenyl group, 2 a pyridyl group,3 a pyrazyl group, 4 a quinolyl group, 5 an indanyl group, 6 acyclohexyl group, 7 a quinoxalyl group, or 8 a furyl group" in thedefinition of R¹ include lower alkyl groups having 1 to 6 carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, andtert-butyl groups; lower alkoxy group corresponding to theabove-described lower alkyl groups, such as methoxy and ethoxy groups; anitro group; halogen atoms such as chlorine, bromine, and fluorine; acarboxyl group; lower alkoxycarbonyl groups corresponding to theabove-described lower alkoxy groups, such as methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl, andn-butyloxycarbonyl groups; an amino group; a lower monoalkylamino group;a lower dialkylamino group, a carbamoyl group; acylamino groups derivedfrom aliphatic saturated monocarboxylic acids having 1 to 6 carbonatoms, such as acetylamino, propionylamino, butyrylamino,isobutyrylamino, valerylamino, and pivaloylamino groups;cycloalkyloxycarbonyl groups such as cyclohexyloxycarbonyl group; loweralkylaminocarbonyl groups such as methylaminocarbonyl andethylaminocarbonyl groups; lower alkylcarbonyloxy groups correspondingto the above-defined lower alkyl groups, such as methylcarbonyloxy,ethylcarbonyloxy, and n-propylcarbonyloxy groups; halogenated loweralkyl groups including a trifluoromethyl group; a hydroxyl group; aformyl group; and lower alkoxy lower alkyl groups such as ethoxymethyl,methoxymethyl, and methoxyethyl groups. The "lower alkyl groups" and"lower alkoxy groups" in the above description of the substituentinclude all the groups derived from the above-mentioned groups. Thesubstituent may be one to three of them which may be the same ordifferent.

Further, when the substituent is a phenyl group, the following group iswithin the scope of the substituted phenyl group: ##STR19## wherein G isa group represented by the formula ##STR20## a group represented by theformula ##STR21## a group represented by the formula --O--, a grouprepresented by the formula ##STR22## a group represented by the formula--CH₂ --O--, a group represented by the formula --CH₂ --SO₂ --,

a group represented by the formula ##STR23## and a group represented bythe formula ##STR24## and E is a carbon or nitrogen atom.

Preferable examples of the substituents for the phenyl group among theminclude lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, loweralkoxycarbonyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups,halogen atoms, and benzoyl and benzylsulfonyl groups. The substituentmay be two or more of them which may be the same or different.

Preferable examples of the substituent for the pyridyl group includelower alkyl and amino groups and halogen atoms.

Preferable examples of the substituent for the pyrazyl group includelower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, andcycloalkyloxycarbonyl groups.

With respect to R¹, the pyridyl group is preferably a 2-pyridyl,3-pyridyl, or 4-pyridyl group; the pyrazyl group is preferably a2-pyrazinyl group; the quinolyl group is preferably a 2-quinolyl or3-quinolyl group; the quinoxalinyl group is preferable a 2-quinoxalinylor 3-quinoxalinyl group; and the furyl group is preferably a 2-furylgroup.

Specific examples of preferable monovalent or divalent group derivedfrom an indanone having an unsubstituted or substituted phenyl ringinclude those represented by the following formulae (II) and (III):##STR25## wherein m's are each an integer of 1 to 4 and A's which may bethe same or different are each one of the substituents described in theabove items 1 to 8 of the definition of R¹ or a hydrogen atom,preferably a hydrogen atom (i.e. unsubstituted), a lower alkyl group, ora lower alkoxy group, and most preferably the indanone group issubstituted or substituted with 1 to 3 methoxy groups.

Examples of the monovalent group derived from a cyclic amide compoundinclude quinazolone, tetrahydroisoquinolinone,tetrahydrobenzodiazepinone, and hexahydroenzazocinone. However, themonovalent group may be any one having a cyclic amide group in thestructural formula thereof and is not limited to the above-describedspecific examples only. The cyclic amide group may be one derived from amonocyclic or condensed heterocyclic ring. The condensed heterocyclicring is preferably one formed by condensation with a phenyl ring. Inthis case, the phenyl ring may be substituted with a lower alkyl grouphaving 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxygroup having 1 to 6 carbon atoms, preferably a methoxy group.

Preferable examples of the monovalent group include the followinggroups: ##STR26## In the above formulae, Y's in the formulae (i) and (l)are each a hydrogen atom or a lower alkyl group, V in the formula (k) isa hydrogen atom or a lower alkoxy group, W¹ and W² in the formulae (m)and (n) are each a hydrogen atom, a lower alkyl group, or a lower alkoxygroup and W³ is a hydrogen atom or a lower alkyl group.

The right-hand ring in each of the formulae (j) and (l) is aseven-membered ring, while the right-hand ring in the formula (k) is aneight-membered ring.

The most preferable examples of the above-defined R¹ include amonovalent group derived from an indanone having an unsubstituted orsubstituted phenyl group and a monovalent group derived from a cyclicamide compound.

The most preferable examples of the above-defined X include a grouprepresented the formula --(CH₂)_(n) --, a group having an amide group,and groups represented by the above formulae wherein n is 2. Therefore,it is most preferable that any portion of a group represented by theformula ##STR27## have a carbonyl or amide group.

The substituents involved in the expressions "a substituted orunsubstituted phenyl group" and "a substituted or unsubstitutedarylalkyl group[ in the above definition of R² are the same as thosedescribed in the above items 1 8 in the above definition of R¹.

The term "arylalkyl group" is intended to mean an unsubstituted benzylor phenethyl group, etc.

Specific examples of the pyridylmethyl group include 2-pyridylmethyl,3-pyridylmethyl, and 4-pyridylmethyl groups.

Preferable examples of R² include benzyl and phenethyl groups. Thesymbol means either a single or a double bond. This bond is a doublebond only when R¹ is the above-described divalent group (III) derivedfrom an indanone having an unsubstituted or substituted phenyl ring,while it is a single bond in other cases.

In the present invention, the term "pharmacologically acceptable salt"include those of inorganic acids, such as hydrochloride, sulfate,hydrobromide, and phosphate, and those of organic acids, such asformate, acetate, trifluoroacetate, methanesulfonate, benzensulfonate,and toluenesulfonate. Further, when a certain kind of substituent isselected, the compound of the present invention may form, e.g., alkalimetal salts such as a sodium or potassium salt, alkaline earth metalsalts such as a calcium or magnesium salt, organic amine salts such as asalt with trimethylamine, triethylamine, pyridine, picoline,dicyclohexylamine, or N,N'-dibenzylethylenediamine.

Moreover, the compounds of the present invention may have an asymmetriccarbon atom depending upon the kind of the substituent and, therefore,have stereoisomers. They are, of course, within the scope of the presentinvention.

One specific example thereof will now be described. When R¹ has anindanone skeleton, the compound of the present invention has anasymmetric carbon atom and, therefore, may have sterioisomers, opticalisomers, diastereomers, etc. All of these isomers are within the scopeof the present invention.

The compound of the present invention may be prepared by variousprocesses. Representative processes for preparing the compound of thepresent invention will now be described.

Process A

When X in the general formula (I) is a group represented by the formula##STR28## wherein n and R⁵ are as defined above, the compound of thepresent invention can be prepared by the following process: ##STR29##

Specifically, a compound (VI) which is one of the object compounds ofthe present invention can easily be prepared by reacting an acyl haliderepresented by the general formula (IV) with a piperidine derivativerepresented by the general formula (V) in the presence of ademineralizing agent, such as sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine,in an organic solvent, such as chloroform, benzene, toluene, dioxane,tetrahydrofuran, or dimethylformamide (DMF), while cooling the reactionmixture or at room temperature or while heating the reaction mixture.

Process B

When R¹ in the general formula (I) is a monovalent or divalent groupderived from an indanone having an unsubstituted or substituted phenylgroup and X is a group represented by the formula --(CH₂)_(n) --,wherein n is an integer of 1 to 6, the compound of the present inventioncan be prepared also by the following process: ##STR30##

Specifically, a compound (X) which is one of the object compounds can beprepared by reacting a substituted 1-indanon-2-ylphosphonate representedby the general formula (VII) with an aldehyde compound represented bythe formula (VIII) i.e., Wittig reaction) to prepare a compound (IX)which is one of the object compounds and then catalytically reducingsaid compound (IX).

Examples of the catalyst used in the Wittig reaction include sodiummethylate (MeONa), sodium ethylate (EtONa), tert-BuOK, and NaH. Examplesof the solvent used in this reaction include tetrahydrofuran (THF),dimethylformamide (DMF), either, nitromethane, and dimethyl sufoxide(DMSO). A reaction temperature ranging from room temperature to about100° C. provides favorable results.

A catalystic reduction in the presence of a catalyst composed ofpalladium-carbon etc. provides favorable results.

The following scheme specifically shows a process for preparing thecompound of the present invention, wherein R¹ is a group represented bythe formula ##STR31## wherein R⁶ and R⁷ may be the same or different andrare each a hydrogen atom, a lower alkyl group, a lower alkylalkoxygroup, or a halogen atom among the groups defined by A, X is a grouprepresented by the formula --(CH₂)_(n) --, wherein n is an integer of 1to 6, R² is a group represented by the formula ##STR32## wherein R⁸ andR⁹ each have the same meaning as that of R⁶ and R⁷ : ##STR33##

Process C

When R¹ in the general formula (I) is a monovalent or divalent groupderived from an indanone having an unsubstituted or substituted phenylgroup and X is a group represented by the formula --(CH₂)_(n) --,wherein n is an integer of 1 to 6, the compound of the present inventioncan be prepared also by the following process: ##STR34##

Specifically, for example, di-isopropylamine and n-butyllithium/hexaneare added to a solvent such as tetrahydrofuran. A substituted 1-indanonerepresented by the general formula (XI) and hexamethylphosphoric amideare added thereto at a temperature of preferably about -80° C. Then analdehyde compound represented by the general formula (VIII) are addedthereto, followed by a reaction according to an ordinary method. Thereaction mixture is subjected to dehydration, thereby preparing acompound (IX). This compound may be catalytically reduced in the samemanner as that of the Process B to prepare a compound (X).

A specific example of the Process C will now be descried in the samemanner as that described in the Process B. ##STR35##

Process D

When R¹ is a monovalent group derived from a cyclic amide compoundselected from among quinazolone, tetrahydroisoquinolinone,tetrahydrobenzodiazepinone, and hexahydrobenzazocinone, the compound ofthe present invention can be prepared also by the following process:##STR36## wherein R¹⁰ and R¹¹ are each a hydrogen atom, a lower alkylgroup, a lower alkoxy group, or a halogen atom, n is an integer of 1 to6, p is an integer of 1 to 3 and Z is a group represented by the formula--CH₂ -- or a group represented by the formula ##STR37## wherein R¹² isa hydrogen atom or a lower alkyl group.

Specifically, a substituted 1,2,3,4-tetrahydro-5H-1-benzazepin-2-one isallowed to condense with a substitutedN-benzyl-4-(2-halogenoethyl)piperidine represented by the generalformula (XIII) in a solvent, e.g., dimethylformamide, in the presenceof, e.g., sodium hydride, thereby preparing a compound (XIV) which isone of the object compounds.

Process E

When R¹ is a group represented by the formula ##STR38## and X is a grouprepresented by the formula --(CH₂)_(n) --, the compound of the presentinvention can be prepared also by the following process: ##STR39##

Specifically, 2-hydroxymethylnicotinic acid lactone (XV) is reacted witha substituted N-benzyl(2-aminoethyl)-piperidine represented by thegeneral formula (XVII) by an ordinary method to prepare a compoundrepresented by the general formula (XVII) which is one of the objectcompounds. The reaction temperature is preferably about 200° C.

Process F

When R¹ in the general formula (I) is a group represented by the formula##STR40## and X is a group represented by the formula --(CH₂)_(n) --,the compound of the present invention can be prepared also by thefollowing process: ##STR41##

Specifically, a substituted 2,3-dihydroxypyrrolo(3,4-b)benzenerepresented by the general formula (XVIII) is reacted with a substitutedN-benzyl(2-halogenoethyl)piperidine represented by the general formula(XIII) in the presence of, e.g., sodium hydride, in a solvent, such asdimethylformamide, while heating the reaction mirture, thereby preparinga compound (XIV) which is one of the object compounds.

Process G

When R¹ in the general formula (I) is a group represented by the formula##STR42## and X is a group represented by the formula --CONH--(CH₂)_(n)--, the compound of the present invention can be prepared also be thefollowing process: ##STR43##

Specifically, 2,3-pyrazylcarboxylic anhydride (XX) is added to, e.g.,isopropyl alcohol, followed by reflux. The alcohol is distilled off, andthe residue is reacted with a substituted N-benzyl(ω-amino-alkyl)piperidine in a solvent, such as tetrahydrofuran, thereby preparing acompound (XXI) which is one of the object compounds.

Process H

When R¹ in the general formula (I) is an unsubstituted or substitutedphenyl group and X is a group represented by the formula ##STR44## or agroup represented by the formula ##STR45## the compound of the presentinvention can be prepared also by the following process: ##STR46##

Specifically, di-isopropylamine and n-butyllithium/hexane are added to asolvent such as tetrahydrofuran. In the presence of this mixture, anacetophenone represented by the general formula (XXII) is allowed tocondense with a substituted N-benzyl(ω-formylalkyl)piperidine, therebypreparing a compound (XXIII). This compound is dehydrated in thepresence of, e.g., p-toluenesulfonic acid in a solvent, such as toluene,followed by catalytic reduction according to an ordinary method, therebypreparing a compound (XXIV) which is one of the object compounds.

Process I procedure 1

The cyclic amine compound having the formula (XXV) in which J is (1)indanyl, (2) indanonyl, (5) indanedionyl, (6) tetralonyl, (7)benzosuberonyl or propyophenyl and B is --(CHR22)r--, ═(CH--CH═CH)b--,═CH--(CH2)c-- or ═(CH--CH)d═ can be produed by the following procedure.B' is a group where the terminal group containing one carbon atom isexcluded from B. ##STR47## In this procedure, the phosphate is reactedwith an aldehyde compound through the Wittig reaction and the product iscatalytically reduced. The catalyst to use in the Wittig reaction,includes sodium methylate, sodium ethylate, potassium t-butyrate orsodium hydride. The reaction may be carried out in a solvent such astetrahydrofuran, dimethylformamide, ether, nitromethane anddimethylsulfoxide at a temperature of the room temperature to 100° C. Inthe catalytical reduction, it is preferable to use a catalyst such as acatalyst of palladium and carbon, Raney nickel and a catalyst of rhodiumand carbon.

In the above shown procedure, one example in which J is indanonyl goes:##STR48##

Procedure 2

The compound as defined in the procedure 1 can be obtained also in thefollowing way. ##STR49## The compound of J-H such as indanone is reactedwith an aldehyde by the conventional Aldol condensation to obtain anintended compound. The reaction may be carried out in a solvent such astetrahydrofuran by first producing lithium di-isopropylamide fromdi-disopropylamine and a n-butylhexane solution of of lithium, addingthereto a compound of J-H at a temperature of preferably about minus 80°C., then adding the aldehyde thereto, effecting the reaction in theconventional way, heating the production mixture up to the roomtemperature to conduct dehydration and obtain the enone body of theintended compound. In another manner, the two reactants are dissolved ina solvent such as tetrahydrofuran, a base such as sodium methylate isadded to the solution at about 0° C. and the reaction is effected at theroom temperature.

The enone body obtained this way can be reduced to obtain the intendedcompound.

One example in which J is indanonyl, B is --(CH2)r-- and T is carbon, Qis nitrogen and q is 2 goes: ##STR50##

Process J

The compound having indanol is produced by the following procedure. Thisprocedure applies to the compound having indanol having a substituent(s)on the phenyl group. ##STR51## The reduction is effected with sodiumboron hydride at 0° C. to the room temperature in a solvent such asmethanol.

Process K

The compound having indenyl is produced by the following procedure. Thisprocedure applies to the compound having indenyl having a substituent(s)on the phenyl. ##STR52## The dehydration is effected conventionally, forexample, with hydrochloric acid.

Process L

The compound having indenonyl is produced by the following procedure.This procedure applies to the compound having indenonyl having asubstituent(s) on the phenyl. ##STR53## The above shown startingcompound having indanone is heated for reflux in a solvent such ascarbon tetrachloride in the presence of N-bromosuccinic imide (NBS) andbenzoyl peroxide to obtain its bromide and the bromide is heated forreflux in a solvent such as tetrahydrofuran with1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to conduct the beta-eliminationand obtain the indenone compound. The bromide may be replaced by anotherhalogenated compound.

The indanone compound, as used in the above shown processes I, J, K andL, is available in the commercial market and is produced by thefollowing procedures. ##STR54##

The aldehyde compound used above is produced by the followingprocedures. ##STR55## The above shown starting compound is converted toits aldehyde and the aldehyde is used for the Wittig reaction toincrease the carbon number contained therein. The Wittig reaction iseffected repeatedly or combined with another kind of the Wittigreaction. This is obvious to a man skilled in the art. The Wittig agentincludes methoxymethylenetriphenylphosphorane to add one carbon atom andformylmethylenetriphenylphosphorane to add to carbon atoms.Methoxymethylenetriphenylphosphorane is obtained by the reaction betweenmethoxymethylenetriphenylphosphonium chloride and n-butyl lithium inether or tetrahydrofuran. Then a ketone compound or an aldehyde compoundis added to the product mixture to obtain its methoxyvinyl compound andthe resulting mixture is treated with an acid to obtain a correspondingaldehyde. One example goes: ##STR56##

When formylmethylenetriphenylphosphorane is used, a solution of astarting ketone or aldehyde in ether, tetrahydrofuran or benzene ismixed with this Wittig agent and the mixture is heated for reflux toobtain an intended compound.

The obtained unsaturated aldehyde compound may be converted to itssaturated compound by the catalytic reduction using a catalyst ofpalladium and carbon, Raney nickel or a catalyst of rhodium and carbon.One example goes: ##STR57##

The compounds thus prepared and acid addition salts thereof representedby the general formula (I) are useful for treatment of various kinds ofsenile dementia, in particular senile dementia of the Alzheimer type.

The invention will be described in view of its therapeutical usefulnesstogether with pharmacologically experimental data.

EXPERIMENTAL EXAMPLE 1 In vitro acetylcholinesterase inhibitory action

A mouse brain homogenate was used as an acetylcholinesterase source andthe esterase activity thereof was determined according to the method ofEllman et al.

Ellman, G. L., Courtney, K. D., Andres, V., and Featherstone, R. M.,(1961) Biochem. Pharmacol., 7, 88-95.

Acetylthiocholine as a substrate, a sample to detect and DTNB were addedto the mouse brain homogenate, followed by incubation. The amount of ayellow substance formed by the reaction between the thiocholine and DTNBwas determined in the absorbance at 412 nm in terms of theacetylcholinesterase activity.

The acetylcholinesterase inhibitory activity of the sample was expressedin terms of inhibitory concentration 50% (IC₅₀).

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                      AChE                                                                          inhibitory                                                                    activity                                                        Compound      IC.sub.50 (μM)                                               ______________________________________                                         1            0.23                                                             4            0.0053                                                           5            0.10                                                             6            0.017                                                            8            0.013                                                            9            0.051                                                           10            0.009                                                           11            0.063                                                           12            0.040                                                           13            0.026                                                           14            0.038                                                           15            0.094                                                           17            0.052                                                           18            0.68                                                            19            0.064                                                           20            0.54                                                            21            50                                                              23            0.072                                                           24            1.1                                                             26            24                                                              27            0.41                                                            29            0.15                                                            31            0.025                                                           33            0.030                                                           45            0.36                                                            48            0.019                                                           52            0.80                                                            54            1.0                                                             56            0.017                                                           62            0.0075                                                          65            0.0016                                                          67            0.10                                                            70            0.28                                                            72            0.020                                                           89            0.018                                                           90            0.035                                                           95            0.085                                                           101           0.11                                                            120           0.19                                                            124           2.8                                                             176           0.004                                                           ______________________________________                                    

EXPERIMENTAL EXAMPLE 2 Ex vivo acetylcholinesterase inhibitory action

A sample to detect was orally administered to rates. After one hour ofthe administration, the cerebral hemispheres were dissected andhomogenized, followed the by determination of the acetylcholinesteraseactivity. The group of rats treated with physiological saline was usedas the control. Inhibition of AChE by samples ex vivo was expressed interms of inhibition percent of the control value. Results are shown inTable 2.

EXPERIMENTAL EXAMPLE 3 Action on passive avoidance learning impairmentinduced by scopolamine

See Z. Bokolanecky & Jarvik: Int. J. Neuropharmacol, 6, 217-222(1967).

Male Wistar rats were used as the test animal and a step-through lightand dark box was used as an apparatus. A sample to detect was orallyadministered one hour before the training and the rates were treatedwith 0.5 mg/kg (i.p.) of scopolamine 30 min. before the training. In atraining experiment, the animal was placed into a light room and, justafter the animal had entered into a dark room, a guillotine door wasclosed, followed by delivery of an electric shock from the gid of thefloor. After six hours, the animal was again placed into a light roomfor a retention experiment, and the time taken for the animal to enterthe dark room was measured for evaluation of the effect of the sample.

The difference in the response time between the physiological salineadministration group and the scopolamine administration group was takenas 100%, and the effect of the sample was expressed in terms of thepercentage antagonism by the sample (Reverse %).

The results are shown in Table 3.

                  TABLE 2                                                         ______________________________________                                                                AChE                                                  Compd.         Dose     inhibitory                                            No.            (mg/kg)  action (%)                                            ______________________________________                                        Saline                  0                                                      4              1       5*                                                                    3       17**                                                                 10       36**                                                                 30       47**                                                  15             10       5                                                                    30       14**                                                                 100      18**                                                  ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Compd.         Dose     Reverse                                               No.            (mg/kg)  %                                                     ______________________________________                                         4             0.125    55                                                                   0.25     36                                                    13             0.25     39                                                                   0.5      27                                                    15             1.0      51                                                                   2.0      30                                                    19             0.5      37                                                                   1.0      39                                                    69             0.5      22                                                                   1.0      38                                                    ______________________________________                                    

The number of animals per dose was 10 to 17. NE: non-effective.

The above-described pharmacological experiments revealed that thecompound of the present invention had a potent acetylcholinesteraseinhibitory action.

Among the compounds (I) of the present invention, the compound whereinR¹ is a group (II) or (III) derived from an indanone having anunsubstituted or substituted phenyl ring is preferable, and the compoundwherein R¹ is a group represented by the general formula (II) are themost preferable. Specifically, particularly a compound wherein R¹ is agroup derived from an indanone having an unsubstituted or substitutedphenyl ring has characteristics such as remarkable difference from theconventional acetylcholinesterase inhibitor in the structure, advantageswith respect to the manufacture of pharmaceutical preparations by virtueof the potent acetylcholinesterase inhibitory action, large widthbetween the main and the side effects, persistent activity, high watersolubility, excellent stability, advantage in formulating intopreparations, high bioavailability and excellent penetration into thebrain.

Therefore, the objects of the present invention are to provide a novelcompound effective for various kinds of dementia and the sequelae ofcerebrovascular diseases, to provide a process for preparing the same,and to provide a novel pharmaceutical comprising the same as aneffective ingredient.

Representative compounds of the present invention (Compd. Nos. 4, 13,15, 19, and 69 in the above Table 3) were applied to toxicity tests onrats. As a result, all the compounds exhibited a toxicity of 100 mg/kgor more, i.e., exhibited no serious toxicity.

The compound of the present invention is effective for treatment,prevention, remission, improvement, etc. of various kinds of seniledementia, particularly senile dementia of the Alzheimer type;cerebrovascular diseases accompanying cerebral apoplexy, e.g. cerebralhemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury,etc.;and aprosexia, disturbance of speech, hypobulia, emotional changes,recent memory disturbance, hallucinatory-paranoid syndrome, behavioralchanges, etc. accompanying encephalitis, cerebral palsy, etc.

Further, the compound of the present invention has a strong and highlyselective acetylcholinesterase action, which renders the compound of thepresent invention useful also as a pharmaceutical based on this kind ofaction.

Specifically, the compound of the present invention is effective for,for example, Huntington's chorea, Pick's disease and delayed ataxia ortardive dyskinesia other than senile dementia of the Alzheimer type.

When the compound of the present invention is used as a pharmaceuticalfor these diseases, it may be orally or parenterally administered. Ingeneral, it is parenterally administered in the form of injections, suchas intravenous, subcutaneous, and intramuscular injections,suppositories, or sublingual tablets. The does will remarkably varydepending upon the symptom; age, sex, weight, and sensitivity ofpatients; method of administration; time and intervals of administrationand properties, dispensing, and kind of pharmaceutical preparations;kind of effective ingredients, etc., so that there is no particularlimitation with respect to the dose. Normally the compound may beadministered in a dose of about 1.0 to 300 mg, preferably 1 to 100 mg,per day per adult, ordinarily in one to four portions.

Pharmaceutical preparations in the dosage form of, e.g., injections,suppositories, sublingual tablets, tablets, and capsules are preparedaccording to a method which is commonly accepted in the art.

In preparing injections, the effective ingredient is blended, ifnecessary, with a pH modifier, a buffer, a suspending agent, asolubilizing agent, a stabilizer, a tonicity agent, a preservative,etc., followed by preparation of an intravenous, subcutaneous, orintramuscular injection according to an ordinary method. In this case,if necessary, it is possible to lyophilize these preparations accordingto an ordinary method.

Examples of the suspending agents include methylcellulose, Polysorbate80, hydroxyethylcellulose, acacia, powdered tragacanth, sodiumcarboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.

Examples of the solubility agent include polyoxyethylene hydrogenatedcastor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, Macrogol, and an ethyl ester of castor oil fatty acid.

Examples of the stabilizer include sodium sulfite, sodium metasulfite,and ether, and examples of the preservative include methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol,and chloroscresol.

EXAMPLES

The present invention will now be described in more detail withreference to the following Examples. It is needless to say that thetechnical scope of the invention of the present invention is not limitedto these Examples only.

In the following examples, all of the NMR values are those of thecompounds measured in free form.

EXAMPLE 1 1-Benzyl-4-[2-[(1-indanon)-2-yl]]ethylpiperidine hydrochloride##STR58##

0.37 g of 1-benzyl-4-[2-[(1-indanon)-2-yl]]-ethylpiperidine wasdissolved in 10 ml of methanol, followed by addition of 0.1 g of 5%rhodium-carbon. The mixture was hydrogenated at room temperature underatmospheric pressure for 25 hr. The catalyst was filtered off, and thefiltrate was concentrated in vacuo. The residue was purified by makinguse of a silica gel column (methylene chloride:methanol=200:1). Theeluate was concentrated in vacuo, and the residue was dissolved inmethylene chloride. A 10% solution of hydrochloric acid in ethyl acetatewas added to the resulting solution, followed by concentration in vacuoto obtain a crystal, which was recrystallized from methanol/IPE toobtain 0.33 g (yield: 80%) of the title compound having the followingproperties:

m.p. (° C.): 244°-225° C.

elementary analysis: C₂₃ H₂₇ NO.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            74.68       7.63   3.79                                          found (%):   74.66       7.65   3.77                                          ______________________________________                                    

EXAMPLE 2 1-Benzyl-4-[2-[(1-indanon)-2-ylidenyl]]ethylpiperidinehydrochloride ##STR59##

0.32 of 60% sodium hydride was washed with hexane, and 10 ml of THF wasadded thereto. A solution of 2.12 g of diethyl 1-indanon-2-ylphosphonatein 30 ml of THF was dropwise added thereto at 0° C. The mixture wasstirred at room temperature for 30 min and again cooled to 0° C.,followed by addition of a solution of 3.43 g of1-benzyl-4-piperidineacetoaldehyde in 10 ml of DMF. The mixture wasstirred at room temperature for 2 hr and at 50° C. for 2 hr and thenrefluxed for 2 hr while heating the mixture. Methanol and 20% sulfuricacid were added at 0° C. to the reaction mixture. 10 min after theaddition, the reaction mixture was made basic with an aqueous sodiumhydroxide solution and extracted with ethyl acetate. The organic phasewas washed with a saturated saline solution, dried over magnesiumsulfate, and concentrated in vacuo. The resulting residue was purifiedby making use of a silica gel column (methylene chloride:methanol=500:1). The eluate was concentrated in vacuo, and the residuewas dissolved in methylene chloride. A 10% solution of hydrochloric acidin ethyl acetate was added to the resulting solution, followed byconcentration in vacuo to obtain 0.78 g (yield: 27%) of the titlecompound. 1.37 of diethyl 1-indanon-2-ylphosphorate was also recovered.

molecular formula; C₂₃ H₂₅ NO.HCl.

¹ H-NMR(CDCl₃)δ; 1.10˜2.13(7H,m), 2.26(2H,t), 2.88(2H,bd), 3.48(2H,s),6.72˜7.07(2H,m), 7.30(5H,s), 7.10˜8.00(5H,m).

EXAMPLE 3

1-benzyl-4-piperidine-carboaldehyde having the formula: ##STR60## wasprepared in the following way.

26 grams of methoxymethylene-triphenylphosphonium chloride was suspendedin 200 ml of anhydrous ether. 1.6 M solution in hexane of n-butyllithium was added dropwise to the suspension at the room temperature.The mixture was stirred at the room temperature for 30 minutes andcooled down to 0° C. Then 30 ml of a solution in anhydrous ether of14.35 g of 1-benzyl-4-piperidone was added to the mixture. It wasstirred at the room temperature for 3 hours and filtered to remove outthe insoluble. The filtrate liquid was concentrated at a reducedpressure. The obtained concentrate was dissolved in ether and extractedwith 1 N hydrochloric acid. An aqueous solution of sodium hydroxide wasadded to the extract to have pH value of 12. The resultant was extractedwith methylene chloride. The extract was dried with magnesium sulfateand concentrated at a reduced pressure. The residue was purified with acolumn filled with silica gel to obtain 5.50 g of an oil with a yield of33 percent.

The oil was incorporated into 40 ml of methanol and 40 ml of 1 Nhydrochloric acid was added to the solution. It was heated so as to makereflux for 3 hours and then concentrated at a reduced pressure. Theresidue was dissolved in water. An aqueous solution of sodium hydroxidewas added to the solution to have a pH value of 12 and the solution wasextracted with methylene chloride. The extract was washed with saturatedsalt solution and dried with magnesium sulfate. It was furtherconcentrated at a reduced pressure and the residue was purified in acolumn charged with silica gel. 2.77 g of the intended compound wasobtained with a yield of 54 percent. In analysis, its molecular formulawas found to be C13H17NO and 1H-NMR (CDCl₃)δ, 1.40-2.40(7H,m), 2.78(2H,dt), 3.45(2H,S), 7.20(5H,S), 9.51(1H,d).

The compound may be produced according to the methods shown in (1) Arm.Kim. Zh., 36(9), 614-17 (1983) by R. A. Kuroyan, A. I. Markosyan, G. M.Snkhchyan and S. A. Vartangan and (2) Ind. Chim, Belge, 32, 64-5 (1967)by B. Hermans and P. Van Daele.

1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]-methylpiperidinehydrochloride ##STR61##

This reaction was conducted in an argon atmosphere.

2.05 ml of diisopropylamine was added to 10 ml of anhydrous THF,followed by addition of 9.12 ml of a 1.6 M solution of n-butyllithium inhexane at 0° C. The mixture was stirred at 0° C. for 10 min and thencooled to -78° C., and a solution of 2.55 g of 5,6-dimethoxy-1-indanonein 30 ml of anhydrous THF and 2.31 ml of hexamethyl-phosphoric amidewere added thereto. The mixture was stirred at -78° C. for 15 min, and asolution of 2.70 g of 1-benzyl-4-piperidinecarboaldehyde in 30 ml ofanhydrous THF was added thereto. The temperature of the mixture wasgradually raised to room temperature, followed by stirring for 2 hr. Anaqueous 1% ammonium chloride solution was added thereto, and the organicphase was separated. The water phase was extracted with ethyl acetate,and the organic phases were combined with each other. The combinedorganic phase was washed with a saturated saline solution, dried overmagnesium sulfate, and concentrated in vacuo. The resulting residue waspurified by making use of a silica gel column (methylene chloride:methanol=500:1-100:1). The eluate was concentrated in vacuo, and theresidue was dissolved in methylene chloride. A 10% solution ofhydrochloric acid in ethyl acetate was added to the resulting solution,followed by concentration in vacuo to obtain a crystal, which wasrecrystallized from methanol/IPE to obtain 3.40 g (yield: 62%) of thetitle compound having the following properties:

m.p. (° C.): 237°-238° C. (dec.).

elementary analysis: C₂₄ H₂₇ NO₃.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            69.64       6.82   3.38                                          found (%):   69.51       6.78   3.30                                          ______________________________________                                    

EXAMPLE 4 1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidinehydrochloride ##STR62##

0.4 g of1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine wasdissolved in 16 ml of THF, followed by addition of 0.04 g of 10%palladiumcarbon. The mixture was hydrogenated at room temperature underatmospheric pressure for 6 hr. The catalyst was filtered off, and thefiltrate was concentrated in vacuo. The residue was purified by makinguse of a silica gel column (methylene chloride: methanol=50:1). Theeluate was concentrated in vacuo, and the residue was dissolved inmethylene chloride. A 10% solution of hydrochloric acid in ethyl acetatewas added to the resulting solution, followed by concentration in vacuoto obtain a crystal, which was recrystallized from methanol/IPE toobtain 0.36 g (yield: 82%) of the title compound having the followingproperties:

m.p. (° C.): 211°-212° C. (dec.).

elementary analysis: C₂₄ H₂₉ NO₃.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            69.30       7.27   3.37                                          found (%):   69.33       7.15   3.22                                          ______________________________________                                    

EXAMPLE 52-[4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-1-oxypyrrolo[3,4-b]pyridinedihydrochloride ##STR63##

12.6 g of 2-hydroxymethylnicotinic acid lactone and 40 g of4-(2-aminoethyl)benzylpiperazine were stirred in a sealed tube at 200°C. for 7 hr. Thereafter, the reaction mixture was purified by making useof a silica gel column, and a hydrochloride of the purified product wasprepared by an ordinary method, thereby preparing 6.37 g ofdihydrochloride of the object compound.

m.p. (°°C.): 143.5°-145° C.

elementary analysis: C₂₁ H₂₅ N₃ O.2HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            61.77       6.66   10.29                                         found (%):   61.49       6.68   9.98                                          ______________________________________                                    

EXAMPLE 62-[4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]benzenehydrochloride ##STR64##

0.5 g of 2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]benzene was dissolvedtogether with a catalytic amount of potassium iodide in DMF. 0.21 g ofsodium hydride (60%) was added to the resulting solution while coolingand stirring the solution. Thereafter, 1 g of2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]-benzene was added thereto,and the mixture was stirred at 80° C. for 4 hr. After the completion ofthe stirring, H₂ O was added thereto, followed by extraction withchloroform. The chloroform phase was washed with water and dried (overMgSO₄). The solvent was distilled off, and the residue was purified withsilica gel, thereby preparing an oleaginous object compound. Ahydrochloride of the object compound was prepared by an ordinary method,thereby obtaining about 0.2 g of a creamy crystal.

molecular formula; C₂₄ H₃₀ N₂ O₃.2HCl.

¹ H-NMR(CDCl₃)δ; 1.12˜3.4(9H,m), 2.72˜3.00(2H,m), 3.48(2H,s),3.62(2H,t), 3.95(6H,s), 4.26(2H,s), 6.90(1H,s), 7.28(6H,s).

EXAMPLE 7 4-[N-(o-Aminobenzyl)ethyl]-1-benzylpiperidine ##STR65##

30 g of 2-nitrobenzaldehyde, 21.4 g of 1-benzyl-4-aminoethylpiperidine,and 100 ml of methanol were stirred in a nitrogen stream at roomtemperature for 3 hr. The resulting reaction mixture was cooled withice, and a solution of 16 g of sodium borohydride in 30 ml of MeOH wasdropwise added thereto. The reaction was allowed to proceed at roomtemperature for an additional 1 hr. The reaction mixture was poured intowater, extracted with methyl chloride, extracted three times with 150 mlof 10% hydrochloric acid, and washed with methylene chloride. Sodiumcarbonate was added to the water phase to adjust a pH value to 10,followed by extraction with methylene chloride. The extract was driedover anhydrous magnesium sulfate, and the solvent was distilled off invacuo, thereby preparing 28.4 g of1-benzyl-4-[N-(o-nitrobenzyl)ethyl]piperidine.

This compound was dissolved in 100 ml of methanol and hydrogenated inthe presence of 3 g of 10% palladium-carbon (hydrous) at a pressure of 4kg/cm², thereby preparing 25.6 of the title compound.

molecular formula; C₂₁ H₂₉ N₃.

¹ H-NMR(CDCl₃)δ; 1.0˜2.1(9H,m), 2.64(2H,t), 2.90(2H,m), 3.47(2H,s),6.65(2H,m), 7.02(2H,m), 7.30(5H,s).

EXAMPLE 8 3-[2-(1-Benzyl-4-piperidyl)ethyl-2-(1H,3H)-quinazolinone##STR66##

25.6 g of 4-[N-(o-aminobenzyl)ethyl]-1-benzylpiperidine, 15 g of1,1'-carbonyldiimidazole, and 100 ml of methanol were heated underreflux for 12 hr. After the completion of the reaction, the reactionmixture was poured into water, extracted with methylene chloride anddried over magnesium sulfate. The solvent was distilled off in vacuotherefrom.

The residue was purified by silica gel column chromatography (5%MeOH-CH₂ Cl₂) and recrystallized twice from ethyl acetate, therebypreparing 3.0 g the title compound.

molecular formula; C₂₂ H₂₇ N₃ O.

¹ H-NMR(CDCl₃)δ; 1.0˜2.1(9H,m), 2.7˜3.0(2H,m), 3.2˜3.6(4H,m), 4.4(2H,s),6.5˜7.4(8H,m), 7.75(1H,s).

EXAMPLE 91-[4'-(1'-Benzylpiperidine)ethyl-1,2,3,4-tetrahydro-4-methyl-5H-[1,4]-benzodiazepin-2-onedihydrochloride ##STR67##

0.35 g of sodium hydride was suspended in 0.5 ml of dimethylformamide(DMF). The suspension was stirred while cooling it with ice, and 0.52 gof 1,2,3,4-tetrahydro-4-methyl-5H-[1,4]-benzodiazepin-2-one dissolved in3 ml of DMF was dropwise added thereto, followed by stirring at roomtemperature for 30 min. 0.81 g of N-benzyl-4-(2-chloromethyl)piperidinehydrochloride dissolved in 3 ml of DMF was dropwise added thereto, andthe mixture was stirred at 60° to 70° C. for 7 hr. The reaction mixturewas poured into ice/water and extracted with methylene chloride. Theextract was washed with a saturated saline solution and dried overmagnesium sulfate. The solvent was distilled off in vacuo. The residuewas purified by silica gel column chromatography. A hydrochloride of thepurified produce was prepared by an ordinary method. Thus there wasobtained 0.17 g of a pale yellow amorphous substance (yield: 13.5%).

molecular formula; C₂₄ H₃₁ N₃ O.2HCl.

¹ H-NMR(CDCl₃)δ; 1.25˜2.20(9H,m), 2.52(3H,s), 2.79˜2.95(2H,bd),3.10(2H,s), 3.43(2H,s), 3.54(2H,s), 3.91(2H,bt), 7.14˜7.45(9H,m).

EXAMPLE 101-[4'-(1'-Benzylpiperidine)ethyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-2-onehydrochloride ##STR68##

0.27 g of sodium hydride was suspended in 0.5 ml of dimethylformamide(DMF). The suspension was stirred while cooling it with ice. 0.60 g of1,2,3,4-tetrahydro-5H-1-benzazepin-2-one dissolved in 4 ml of DMF wasdropwise added thereto. The mixture was heated at 60° C. for 15 min andthen cooled with ice. 1.02 g of N-benzyl-4-(2-chloromethyl)piperidinehydrochloride was added thereto, and the mixture was stirred at 60° C.for 3.5 hr. The reaction mixture was left to stand for cooling, pouredinto ice/water, and extracted with methylene chloride. The extract waswashed with water and dried over magnesium sulfate. The solvent wasdistilled off in vacuo. The residue was purified by silica gel columnchromatography. A hydrochloride of the purified product was prepared byan ordinary method. Thus there was obtained 1.40 g of the title compound(yield 94.8%).

molecular formula; C₂₄ H₃₀ N₂ O.HCl.

¹ H-NMR(CDCl₃)δ; 1.20˜1.92(11H,m), 2.20˜2.24(4H,bs), 2.60˜2.88(4H,m),3.44(2H,s), 7.12˜7.24(9H,m).

EXAMPLE 11N-[4-(1'-Benzylpiperidyl)ethyl]-5,6,11,12-tetrahydrodibenzo[b,f]azocin-6-onehydrochloride ##STR69##

2.24 g of 5,6,11,12-tetrahydrobenzo[b,f]azocin-6-one and 60% sodiumhydride were added to 20 ml of dimethylformamide. The mixture wasstirred at 60° C. for 1 hr, and 0.7 g of1-benzyl-4-chloroethylpiperidine was added thereto, followed by thereaction for an additional 3.5 hr.

The reaction mixture was poured into 20 ml of water extracted with ethylacetate, washed with a saturated saline solution, and dried overmagnesium sulfate. The solvent was distilled off therefrom in vacuo.

The residue was purified by silica gel column chromatography (5% MeOH inCH₂ Cl₂), thereby preparing 0.6 g of the title compound.

molecular formula; C₂₉ H₃₂ N₂ O.HCl.

¹ H-NMR(CDCl₃)δ; 1.1˜2.2(9H,m), 3.7˜4.1(4H,m), 4.15˜4.5(2H,m),4.46(2H,s), 6.8˜7.4(13H,m).

EXAMPLE 1210-[4'-(1'-Benzylpiperidine)ethyl]-10,11-dihydro-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-onehydrochloride ##STR70##

0.25 g of sodium hydride was suspended in dimethylformamide (DMF). Thesuspension was stirred while cooling it with ice. 0.58 g of10,11-dihydro-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-one dissolved in5 ml of DMF was dropwise added thereto. The mixture was stirred at 40°to 50° C. for 20 min and then cooled with ice. 0.71 g of4-(aminoethyl)-1-benzylpiperidine was added thereto, and the mixture wasstirred at 45° to 55° C. for 6 hr. The reaction mixture was poured intoice/water and extracted with methylene chloride. The organic phase waswashed with a saturated saline solution and dried over magnesiumsulfate. The solvent was distilled off in vacuo. The residue waspurified by silica gel column chromatography. A hydrochloride of thepurified product was prepared by an ordinary method. Thus there wasobtained 0.78 g of a pale yellow amorphous substance (yield: 65.4%).

molecular formula; C₂₈ H₃₁ N₃ O.HCl.

¹ H-NMR(CDCl₃)δ; 1.20˜1.91(11H,m), 2.60˜3.00(2H,bs), 3.22(3H,s),3.41(2H,s), 6.87˜7.08(3H,m), 7.08(9H,m), 7.64(1H,dd).

EXAMPLE 13 Isopropyl3-[[4'-(1'-benzylpiperidine)propionyl]amino]-2-pyrazinecarboxylatehydrochloride ##STR71##

18 g of 2,3-pyrazinecarboxylic anhydride was added to 200 ml ofisopropyl alcohol, and the mixture was refluxed for 1 hr. Thereafter,the alcohol was distilled off therefrom. The resulting solid wasdissolved in THF, and 30.6 g of 4-(2-aminoethyl)benzylpiperidine and 21g of 1-hydroxybenzotriazole were added thereto. The mixture was stirredwhile cooling, and 29.7 g of DCC was added to the mixture, followed by areaction at room temperature overnight. The reaction mixture wasfiltered and THF was distilled off from the filtrate, followed byaddition of methylene chloride. The mixture was washed with an aqueoussaturated potassium carbonate solution and then with a saline solutionand dried. The solvent was distilled off therefrom. The residue waspurified by making use of a silica gel column. The resulting crystal wasrecrystallized from ether-hexane, thereby preparing 8.81 g of a whitecrystal of the object compound. A hydrochloride of the compound wasprepared by an ordinary method.

elementary analysis: C₂₃ H₃₀ N₄ O₃.HCl.1/2H₂ O.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            60.58       7.07   12.29                                         found (%):   60.54       7.00   12.29                                         ______________________________________                                    

EXAMPLE 14N-[4'-(1'-(p-Hydroxybenzyl)piperidine)ethyl]-2-quinoxalinecarboxylicamide hydrochloride ##STR72##

2 g of 2-quinoxalinecarboxylic acid chloride was reacted with 2.52 g of1-(p-methoxybenzyl)-4-piperidineethylamine in the presence of 2 g oftriethylamine in THF at room temperature. The reaction mixture waspost-treated by an ordinary method and purified by columnchromatography, thereby preparing 2.5 g ofN-[4'-(1'-(p-methoxybenzyl)piperidine)ethyl]-2-quinoxalinecarboxylicamide.

This compound was dissolved in 1 g of methylene chloride and reactedwith BBr₃ for demethylation. The product was purified by columnchromatography, thereby preparing 0.3 g of a product. A hydrochloride ofthe product was prepared to obtain 0.2 g of a creamy crystal.

molecular formula; C₂₃ H₂₆ N₄ O₂.HCl.

¹ H-NMR(CDCl₃)δ; 1.08˜1.92(9H,m), 2.84˜3.18(2H,m), 3.24˜3.64(2H,m),3.52(2H,s), 6.60(2H,d), 7.05(2H,d), 7.17(2H,s), 7.64˜8.14(4H,m),9.53(1H,m).

EXAMPLE 15 N-[4'-(1'-Benzylpiperidyl)ethyl]-2-quinoxalinecarboxylicamide ##STR73##

40 g of 2-quinoxaloyl chloride was added to a mixture of 4.6 g of1-benzyl-4-aminoethylpiperidine, 50 ml of pyridine, and4-dimethylaminopyridine while stirring the mixture at room temperature,followed by a reaction for 3 hr. Thereafter, the reaction mixture waspoured into water, extracted with methylene chloride, and dried overanhydrous magnesium sulfate. The solvent was distilled off therefrom.

The residue was purified by silica gel chromatography (5% MeOH--CH₂ Cl₂)and recrystallized from ethyl acetate, thereby preparing 3.0 g of thetitle compound.

molecular formula; C₂₃ H₂₆ N₄ O₂.HCl.

¹ H-NMR(CDCl₃)δ; 1.16˜2.20(9H,m), 2.76˜3.04(2H,m), 3.49(2H,s),3.48˜3.68(2H,t), 7.13˜7.40(5H,m). 7.70˜8.26(4H,m), 9.64(1H,s).

EXAMPLE 16 1-Benzyl-4-(N'-phenylaminoethyl)piperidine ##STR74##

47 g of 4-(N-benzoylpiperidyl) acetate, 8 ml of thionyl chloride, and 20ml of benzene were heated under reflux for 2 hr. Thereafter, the solventwas distilled off in vacuo.

The residue wad dissolved in 20 ml of THF. The resulting solution wasdropwise added to a mixture of 1.86 g of aniline, 10 g of triethylamine,and 30 ml of THF while cooling the mixture with ice and, at the sametime, stirring the mixture, followed by a reaction at room temperaturefor about 11 hr. The reaction mixture was poured into water andextracted with methylene chloride. The extract was washed with asaturated saline solution and dried over magnesium sulfate. The solventwas distilled off in vacuo. The residue was purified by silica gelchromatography (5% MeOH, in CH₂ Cl₂) to prepare 0.9 g of4-(N-benzoylpiperidyl)acetanilide.

0.9 g of 4-(N-benzoylpiperidyl)acetanilide was dissolved in 10 ml ofTHF. A solution of 0.38 g of lithium aluminum hydride in 30 ml of THFwas dropwise added to the resulting solution while cooling and stirringthe solution. The mixture was heated under reflux for additional 1 hr.After the completion of the reaction, water was added thereto. Theresulting precipitate was removed by filtration. The filtrate wasextracted with ethyl acetate, washed with a saturated saline solution,and dried over anhydrous magnesium sulfate. The solvent was distilledoff in vacuo to prepare 0.7 of1-benzyl-4-(N'-phenylaminoethyl)piperidine.

molecular formula; C₂₀ H₂₆ N₂.

¹ H-NMR(CDCl₃)δ; 1.0˜2.2(9H,m), 2.85(2H,m), 3.10(2H,t), 3.44(2H,s),3.7(1H,bs), 6.4˜6.8(3H,m), 7.0˜7.4(7H,m).

EXAMPLE 17 N-[4'-(1'-Benzylpiperidyl)ethyl]acetanilide ##STR75##

0.4 g of acetyl chloride was dropwise added to a mixture of 0.7 g of1-benzyl-4-(N'- phenylaminoethyl)piperidine, 2.0 g of triethylamine, and20 ml of THF while cooling the mixture with ice under stirring.

The reaction was allowed to proceed at room temperature for 3 hr, and 20ml of water was added thereto, followed by extraction with methylenechloride. The extract was washed with a saturated saline solution anddried over anhydrous magnesium sulfate. The solvent was distilled offtherefrom in vacuo. The residue was purified by column chromatography(5% MeOH in CH₂ Cl₂), thereby preparing the title compound.

molecular formula; C₂₃ H₂₈ N₂ O.

¹ H-NMR(CDCl₃)δ; 1.0˜2.1(12H,m), 2.6˜3.0(2H,m), 3.39(2H,s), 3.67(2H,t),6.9˜7.5(10H,m).

EXAMPLE 18 N-(3'5'-Dimethoxyphenyl)-N-[4'-(1'-benzylpiperidyl)ethyl]-4-fluorocinnamamide hydrichloride ##STR76##

0.51 g of p-fluorocinnamoyl chloride was added to a mixture of 1.0 g of1-benzyl-4-[N'-(3',5'-dimethoxyphenyl)aminoethyl]piperidine, 2.0 g oftriethylamine, and 20 ml of THF while cooling the mixture with ice understirring. The reaction was allowed to proceed at room temperature for 2hr. Thereafter the reaction mixture was poured into water, extractedwith ethyl acetate, washed with a saturated saline solution, and driedover anhydrous magnesium sulfate. The solvent was distilled offtherefrom in vacuo.

The residue was purified by silica gel chromatography (5% MeOH in CH₂Cl₂). A hydrochloride of the product was prepared by an ordinary method,thereby obtaining 0.9 g of the title compound.

molecular formula; C₃₁ H₃₅ N₂ O₃ F.HCl.

¹ H-NMR(CDCl₃)δ; 1.1˜2.1(9H,m), 2.7˜3.0(2H,bd), 3.51(2H,s), 3.83(8H,m),6.1˜6.4(4H,m), 6.9˜7.8(10H,m).

EXAMPLE 19 N-[4'-(1'-Benzylpiperidine)ethyl]-N-phenylnicotinamiddihydrochloride ##STR77##

0.70 g of N-[4'-(1'-benzylpiperidine)ethyl]aniline and a catalyticamount of 4-(N,N-dimethylamino)pyridine were dissolved in 30 ml ofpyridine. The resulting solution was stirred while cooling it with ice.0.85 g of isonicotinoyl chloride was added thereto, followed by stirringfor 3.5 hr. The solvent was distilled off in vacuo. The residue waspurified by making use of a silica gel column. A dihydrochloride of thepurified product was prepared by an ordinary method. Thus there wasobtained 0.75 g of a pale yellow amorphous substance (yield: 73.0%).

molecular formula; C₂₆ H₂₉ N₃ O.2HCl.

¹ H-NMR(CDCl₃)δ; 1.13˜2.01(9H,m), 2.81(2H,bd), 3.44(2H,s), 3.88(2H,bt),6.84˜7.26(12H,m), 8.31(2H,d).

EXAMPLE 20 4-(1-Benzylpiperidine)propananilide hydrochloride ##STR78##

0.5 g of aniline and 1 g of triethylamine were dissolved in THF. 1 g of4-(1-benzylpiperidine)propionyl chloride was dropwise added to theresulting solution while stirring the solution, followed by a reactionat room temperature for 5 hr. Thereafter the solvent was distilled offand methylene chloride was added to the residue. The resulting solutionwas washed with water and dried over MgSO₄. The solvent was againdistilled off and the residue was purified by making use of a silica gelcolumn, thereby preparing the object compound in the form of oleaginousmatter. A chloride of this compound was prepared by an ordinary method,thereby obtaining 0.14 g of a white crystal.

m.p. (°°C.): 197.5°-198° C.

elementary analysis: C₂₁ H₂₆ N₂ C.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%):                                                                            70.28       7.58   7.81                                          found (%):   70.50       7.58   7.83                                          ______________________________________                                    

EXAMPLE 21 N-[3'-(1'-Benzylpyrrolidine)methyl]benzamide hydrochloride##STR79##

0.74 g of benzyl chloride was reacted with 1 g of3-(2'-aminomethyl)benzylpyrrolidine in the presence of 1.5 g oftriethylamine in THF at room temperature while stirring the reactionsystem. The reaction mixture was post-treated by an ordinary method andpurified by column chromatography, thereby preparing 0.32 g of theobject compound. A hydrochloride of the compound was prepared by anordinary method.

molecular formula; C₁₉ H₂₂ N₂ O.HCl.

¹ H-NMR(CDCl₃)δ; 1.48˜3.08(7H,m), 3.44(2H,d), 3.62(2H,d),7.04˜7.88(10H,m).

EXAMPLE 22 4-[4'-(N-Benzyl)piperidyl]-3-hydroxy-p-methoxybutyrophenone##STR80##

2 ml of diisopropylamine was added to 7 ml of THF in a nitrogen stream.7.6 ml of a 1.6 M solution of n-butyllithium in hexane was added theretoat 0° C. The mixture was stirred for 10 min and then cooled to -78° C. Asolution of 1.65 g of p-methoxyacetophenone in 10 ml of THF was addedthereto, and the mixture was stirred for 20 min. Further, a solution of2.4 g of 1-benzyl-4-piperidinecarboaldehyde in 10 ml of THF was addedthereto, and the mixture was stirred for 10 min. An aqueous 1% ammoniumchloride solution was added to the reaction mixture, followed byextraction with methylene chloride. The extract was washed with asaturated saline solution and dried over anhydrous magnesium sulfate.The solvent was distilled off in vacuo. The residue was purified bysilica gel column chromatography (5% MeOH--CH₂ Cl₂), thereby preparing2.0 g of the title compound.

molecular formula; C₂₃ H₂₉ NO₃.

¹ H-NMR(CDCl₃)δ; 1.0˜2.2(9H,m), 2.6˜3.4(5H,m), 3.43(2H,s), 3.81(3H,s),4.1(1H), 6.83(2H,d), 7.17(5H,s), 7.82(2H,d).

EXAMPLE 23 4-[4'-N-Benzyl)piperidyl]-p-methoxybutyrophenonehydrochloride ##STR81##

0.54 g of 4-[4'-(N-benzyl)piperidyl]-3-hydroxy-p-methoxybutyrophenone,0.1 g of p-toluenesulfonic acid, and 30 ml of toluene were heated underreflux for 5 hr by making use of a Dean-Stark reflux condenser. Afterthe completion of the reaction, the reaction mixture was poured into anaqueous potassium carbonate solution, extracted with methylene chloride,and dried over anhydrous magnesium sulfate. The solvent was distilledoff in vacuo. The residue was purified by column chromatography (5%MeOH-CH₂ Cl₂) to prepare 0.45 g of1-benzyl-4-[4-(p-methoxyphenyl)-4-oxobutyl]-piperidine. This compoundwas dissolved in 20 ml of MeOH and 40 mg of 10% palladium-carbon(anhydrous) was added thereto to effect hydrogenation at roomtemperature under atmospheric pressure for 1.5 hr. The insolubles werefiltered off, and the solvent was distilled off in vacuo. Ahydrochloride of the product was prepared by an ordinary method. Thehydrochloride was recrystallized from MeOH-IPE, thereby preparing 0.2 gof the title compound.

molecular formula; C₂₂ H₂₉ NO₂.HCl.

¹ H-NMR(CDCl₃)δ; 1.4˜2.3(11H,m), 2.4˜2.7(2H,m), 2.95(2H,t), 3.55(2H,s),3.87(3H,s), 6.93(2H,d), 7.1˜7.5(5H,m), 7.94(2H,d).

EXAMPLE 24 N-[4'-(1'-Benzylpiperidine)ethyl]-3-furancarboxylic amidehydrochloride ##STR82##

1.64 g of 4-(2-aminoethyl)-1-benzylpiperidine and 2.67 g of potassiumcarbonate were added to a mixture comprising 40 ml of chloroform and 40ml of water. The mixture was stirred for 1 hr while cooling it with ice.The organic phase was separated, washed with a saturated salinesolution, and dried over magnesium sulfate. The solvent was distilledoff in vacuo and the residue was purified by making use of a silica gelcolumn. A hydrochloride of the product was prepared by an ordinarymethod, thereby obtaining 1.60 g of the title compound in the form of apale yellow amorphous substance (yield: 61.1%).

molecular formula; C₁₉ H₂₄ N₂ O₂.HCl.

¹ H-NMR(CDCl₃)δ; 1.47˜2.10(9H,m), 2.81(2H,bd), 3.25˜3.47(4H,m),5.80(1H,bs), 6.51(1H,dd), 7.15˜7.19(6H,m), 7.82(1H,dd).

EXAMPLE 25 N-[4'-Benzylpiperidine)ethyl]benzamide ##STR83##

1.47 g of N-(1-adamantanemethyl)-4-(2-aminoethyl)piperidine and 0.73 gof potassium carbonate were added to a mixture comprising 15 ml ofchloroform and 15 ml of water. The mixture was vigorously stirred whilecooling it with ice. 0.90 g of benzoyl chloride was added to themixture, followed by stirring at room temperature overnight. The organicphase was separated, washed with water and a saturated saline solution,and dried over magnesium sulfate. The solvent was distilled off invacuo. The residue was purified by making use of a silica gel column.The purified product was recrystallized from benzene-n-hexane, therebypreparing 1.47 g of the title compound in the form of a pale yellowplate crystal (yield: 72.6%).

molecular formula; C₂₅ H₃₆ N₂ O.

¹ H-NMR(CDCl₃)δ; 1.29˜2.28(27H,m), 2.72(2H,bs), 3.43(2H,q), 6.01(1H,bs),7.31˜7.43(3H,m), 7.67(1H,dd).

EXAMPLE 26 N-Methyl-N-[4'-(1'-benzylpiperidine)ethyl]benzamidehydrochloride ##STR84##

0.18 g of sodium hydride was suspended in 2 ml of tetrahydrofuran (THF).The suspension was stirred while cooling it with ice. A solution of 1.45g of N-[4'-(1'-benzylpiperidine)ethyl]benzamide dissolved in 5 ml of THFwas dropwise added thereto. The mixture was stirred at room temperaturefor 1 hr and again cooled with ice. 0.36 ml of methyl iodide was addedthereto, followed by stirring at room temperature overnight. Thereaction mixture was poured into ice/water, extracted with chloroformwhile conducting salting out, washed with a saturated saline solution,and dried over magnesium sulfate. The solvent was distilled off in vacuoand the residue was purified by silica gel chromatography. Thus therewas prepared 0.60 g of yellow oleaginous matter (yield: 47.0%).

The starting material (0.22 g) remaining unmethylated was recovered(recovery: 15.2%). A hydrochloride of the obtained oleaginous matter wasprepared by an ordinary method, thereby obtaining 0.52 g of the titlecompound in the form of a yellow amorphous substance (yield: 37.6%).

molecular formula; C₂₆ H₃₈ N₂ O.HCl.

¹ H-NMR(CDCl₃)δ; 0.92˜3.60(63H,m), 7.29(5H,s).

EXAMPLE 27 N-[4'-(1'-Cyclohexylmethylpiperidyl)ethyl]-N-methylbenzamidehydrochloride ##STR85##

0.6 g of N-methyl-N-(4'-piperidylethyl)benzamide, 1.2 g of cyclohexylbromide, 2.0 g of sodium bicarbonate, and 30 ml of methyl ethyl ketonewere heated under reflux for 7 hr. After the completion of the reaction,water was added to the reaction mixture, followed by extraction withethyl acetate. The extract was washed with a saturated saline solutionand dried over anhydrous magnesium sulfate. The solvent was distilledoff in vacuo. The residue was purified by silica gel chromatography (5%MeOH--CH₂ Cl₂), thereby preparing 0.3 g of the title compound.

molecular formula; C₂₂ H₃₄ N₂ O.HCl.

¹ H-NMR(CDCl₃)δ; 0.8˜1.1(20H,m), 1.1˜1.6(4H,m), 1.8˜2.6(5H,m),7.4(5H,s).

EXAMPLES 28 to 177

The compound synthesized in the same manner as that of Examples 1 to 27are shown in Tables 4 to 8.

    TABLE 4      Ex. No. Structural formula Physicochemical constant (m.p., elem. anal.,     NMR, etc.)          28      ##STR86##      m.p. (°C.); 247˜248 (dec.)elem. anal.: C.sub.23 H.sub.27     NO.sub.3.HClCHNcalcd. (%) 68.73 7.02 3.48found(%) 68.70 6.99 3.35  29      ##STR87##      m.p. (°C.); 196˜197elem. anal.: C.sub.22 H.sub.25          c      NO.HClCHNalcd. (%) 74.24 7.36 3.94found(%) 74.25 7.56 3.80      30     ##STR88##      m.p. (°C.); 203˜204 (dec.)elem. anal.: C.sub.23 H.sub.27     NO.sub.2.HClCHNcalcd. (%) 71.58 7.31 3.63found(%) 71.58 7.25 3.65  31      ##STR89##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜3.40(14H, m), 3.48(2H, s),     3.81(3H, s),3.85(3H, s), 3.85(3H, s), 6.25(1H, bs),6.42(1H, bs),     7.25(5H, s)mol. form.; C.sub.24 H.sub.29 NO.sub.3.HCl      32     ##STR90##      .sup.1 H-NMR(CDCl.sub.3)δ;1.05˜3.40(14H, m), 3.45(2H, s),     3.80(3H, s),3.85(3H, s), 6.75(2H, ABq), 7.22(5H, s)mol. form.; C.sub.24     H.sub.29 NO.sub.3.HCl      33     ##STR91##      m.p. (°C.); 201˜202 (dec.)elem. anal.: C.sub.25 H.sub.31     NO.sub.3.HClCHNcalcd.(%) 69.83 7.50 3.26found(%) 69.13 7.42 3.311/5H.sub.     2 O (%) 69.25 7.53 3.23      34     ##STR92##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜3.40(11H, m), 3.50(2H, s),     3.85(3H, s),3.93(3H, s), 4.25(1H, bs), 6.81(1H, s),7.07(1H, s), 7.22(5H,     s)mol. form.; C.sub.23 H.sub.27 NO.sub.4      35     ##STR93##      m.p. (°C.); 225˜226 (dec.)elem. anal.: C.sub.23 H.sub.25     NO.sub.3.HClCHNcalcd. (%) 69.08 6.55 3.50found(%) 68.78 6.43 3.50  36      ##STR94##      m.p. (°C.); 169˜170 (dec.)elem. anal.: C.sub.22 H.sub.23     NO.HClCHNcalcd. (%) 74.67 6.84 3.96found(%) 74.42 6.61 3.76      37     ##STR95##      m.p. (°C.); 120˜122elem. anal.: C.sub.23 H.sub.25      NO.sub.2.HClCHNcalcd. (%) 71.96 6.83 3.65found(%) 71.84 6.85 3.46  38      ##STR96##      .sup.1 H-NMR(CDCl.sub.3)δ;1.40˜2.40(7H, m), 2.90(2H, bd),     3.48(2H, s),3.51(2H, bd), 3.82(3H, s), 3.86(3H, s), 6.30(1H, bd),     6.43(1H, bd), 6.50(1H, bt), 7.23(5H, s)mol. form.; C.sub.24 H.sub.27     NO.sub.3.HCl      39     ##STR97##      .sup.1 H-NMR(CDCl.sub.3)δ;1.40˜2.50(7H, m), 2.86(2H, bd),     3.50(4H, s),3.90(3H, s), 3.94(3H, s), 6.59(1H, dt),6.78(2H, ABq),     7.22(5H, s)mol. form.; C.sub.24 H.sub.27 NO.sub.3.HCl      40     ##STR98##      .sup.1 H-NMR(CDCl.sub.3)δ;1.14˜2.04(14H, m), 3.49(2H, s),     3.81(6H, s),4.77(3H, dd), 6.65(1H, d), 6.82(1H, d),7.23(5H, s)mol.     form.; C.sub.24 H.sub.31 NO.sub.3.C.sub.4 H.sub.4 O.sub.4      41     ##STR99##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜2.32(9H, m), 2.90(2H, bd),     3.52(4H, s),3.89(3H, s), 3.93(3H, s), 6.71(1H, tt),6.84(1H, s), 7.20(1H,     s), 7.24(5H, s)mol. form.; C.sub.25 H.sub.29 NO.sub.3.HCl      42     ##STR100##      m.p. (°C.); 149˜150elem. anal.: C.sub.22 H.sub.27          c      NO.HClCHNalcd.(%) 73.83 7.88 3.91found(%) 71.29 8.00 3.807/10H.sub.2 O     (%) 71.31 8.00 3.78      43     ##STR101##      .sup.1 H-NMR(CDCl.sub.3)δ;1.80˜2.03(13H, m), 2.80(3H, bd),     3.43(2H, s),4.60(1H, t), 7.28(5H, s), 7.30(5H, s)mol. form.; C.sub.22     H.sub.29 NO.HCl      44     ##STR102##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜2.13(7H, m), 2.26(2H, t),     2.88(2H, bd),3.48(2H, s), 6.72˜7.07(2H, m), 7.30(5H, s),7.10˜     8.00(5H, m)mol. form.; C.sub.22 H.sub.25 NO.HCl      45     ##STR103##      m.p. (°C.); 176˜178elem. anal.: C.sub.21 H.sub.26 N.sub.2     O.2HClCHNcalcd.(%) 63.80 7.14 7.09found(%) 63.13 7.43 6.883/10H.sub.2 O     (%) 62.94 7.19 6.99      46     ##STR104##      .sup.1 H-NMR(CDCl.sub. 3)δ;1.05˜2.15(9H, m), 2.85(2H, bd),     3.02(2H, d),3.25(1H, bs), 3.47(2H, s), 4.10˜4.45(1H, m),7.21(5H,     s), 7.62(2H, dd), 8.70(2H, dd)mol. form.; C.sub.21 H.sub.26 N.sub.2     O.sub.2      47     ##STR105##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜2.10(7H, m), 2.25(2H, bd),     2.85(2H, bd),3.45(2H, bs), 6.59˜7.10(2H, m), 7.20(5H, s),7.56(2H,     dd), 8.67(2H, dd)mol. form.; C.sub.21 H.sub.24 N.sub.2 O.2HCl  48      ##STR106##      m.p. (°C.); 240˜240.7elem anal.: C.sub.20 H.sub.25 N.sub.3     O.2HClCHNcalcd.(%) 66.75 7.28 11.68found(%) 66.26 7.42 11.373/20H.sub.2     O (%) 66.25 7.31 11.59      49     ##STR107##      .sup.1 H-NMR(CDCl.sub.3)δ;1.80˜2.24(9H, m), 2.96(2H, d),     3.64(1H, m),4.60(1H, m), 7.20˜7.58(6H, m), 8.34(2H, d)mol. form.;     C.sub.19 H.sub.21 N.sub.3 O.sub.2.HCl      50     ##STR108##      .sup.1 H-NMR(CDCl.sub.3)ε;1.12˜2.20(7H, m), 2.34(2H, d),     2.74˜3.01(2H,m), 3.50(2H, s), 7.29(2H, s), 7.71(2H, d),8.20(2H,     d)

                                      TABLE 5                                     __________________________________________________________________________    Ex.                                     Physicochemical constant              No.                                                                              Structural formula                   (m.p., elem. anal., NMR,              __________________________________________________________________________                                            etc.)                                 51                                                                                ##STR109##                          m.p. (°C.); 135˜140                                              (dec.) elem. anal.: C.sub.22                                                  H.sub.25 N.sub.3 O.2HCl CHN                                                   calcd.%) 62.86 6.47 10.00                                                     found(%) 59.22 6.63  9.14                                                     3/2H.sub.2 O (%) 59.06 6.76                                                   9.39                                  52                                                                                ##STR110##                          m.p. (°C.); 80˜82                                                (dec.) elem. anal.: C.sub.22                                                  H.sub.27 N.sub.3 O.2HCl CHN                                                   calcd.%) 62.56 6.92  9.95                                                     found(%) 60.14 7.313 9.21                                                     1.H.sub.2 O (%) 60.00 7.09  9.54      53                                                                                ##STR111##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.2(9H, m),                                                         2.7˜3.1(2H, m), 3.50(2H, s)                                             .03(2H, t), 6.50(1H, m),                                                      6.9˜7.9(9H, m), 8.47(1H, d)                                             ol. form.; C.sub.23 H.sub.26                                                  N.sub.2 O.HCl                         54                                                                                ##STR112##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.2(9H, m),                                                         2.7˜3.1(4H, m),                                                         3.4˜3.7 (6H, m),                                                        7.0˜7.6(8H, m), 8.06(1H, m)                                             ol. form.; C.sub.23 H.sub.28                                                  N.sub.2 O.HCl                         55                                                                                ##STR113##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.20(11H, m), 2.27(3H,                                             m), 2.93(2H, bd), 3.48˜3.70(                                            4H, m), 7.27(5H, s),                                                          7.28˜8.12 (4H, m) mol.                                                  form.; C.sub.24 H.sub.29 N.sub.3                                              O.sub.2.HCl                           56                                                                                ##STR114##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.20(9H, m)2.93(2H,                                                bd), 3.40˜3.65 (6H, m),                                                 4.43(2H, s), 7.00˜7.50(4H,                                              m), 7.31(5H, s) mol. form.;                                                   C.sub.23 H.sub.28 N.sub.2 O.HCl       57                                                                                ##STR115##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.20(9H, m),                                                       2.22˜2.97(8H, m), 3.45(2H,                                              s), 3.55(2H, s),                                                              6.90˜7.20(4H, m), 7.20(5H,                                              s) mol. form.; C.sub.23 H.sub.30                                              N.sub.2.2HCl                          58                                                                                ##STR116##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.16(13H, m),                                                      2.16˜2.50(2H, m), 2.87 (2H,                                             bd), 3.03˜3.43(4H, m),                                                  3.48(2H, s), 7.27(5H, s) mol.                                                 form.; C.sub.19 H.sub.20 N.sub.2                                              O.HCl                                 59                                                                                ##STR117##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.10(9H, m), 1.46(3H,                                              d), 2.87(2H, bd), 3.35˜3.72(                                            3H, m), 3.46(2H, s), 4.40(2H,                                                 dd), 7.00˜7.38(4H, m),                                                  7.28(5H, s) mol. form.; C.sub.24                                              H.sub.30 N.sub.2 O.HCl                60                                                                                ##STR118##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.20˜2.84(2H, m), 3.44(2H,                                              s), 7.14˜7.25 (9H, m)  mol.                                             form.; C.sub.25 H.sub.32 N.sub.2                                              O.HCl                                 61                                                                                ##STR119##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.44˜1.80(15H, m), 2.96(2H,                                             bs), 2.56(2H, s), 7.08˜7.40(                                            9H, m) mol. form.; C.sub.23                                                   H.sub.28 N.sub.2 O.HCl                62                                                                                ##STR120##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.24˜2.50(5H, m), 2.18(2H,                                              bs), 2.54˜2.88 (4H, m),                                                 3.44(2H, s), 3.76(3H, s),                                                     6.64˜6.76 (2H, m), 6.99(1H,                                             d), 7.20(5H, s) mol. form.;                                                   C.sub.25 H.sub.32 N.sub.2                                                     O.sub.2.HCl                           63                                                                                ##STR121##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.25˜2.20(15H, m), 2.58(2H,                                             bt), 2.86(2H, bs), 3.48(2H, s),                                               3.75(3H, s), 6.56˜6.68(2H,                                              m), 7.00(1H, d), 7.21(5H, s) mol.                                             form.; C.sub.25 H.sub.32 N.sub.2                                              O.sub.2.HCl                           64                                                                                ##STR122##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.38-2.02(12H, m), 2.96(2H, d),                                               5.60(2H, s), 4.94(4H, m),                                                     7.08˜7.36(9H, m) mol.                                                   form.; C.sub.23 H.sub.29 N.sub.3                                              O.HCl                                 65                                                                                ##STR123##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.32˜2.36(15H, m),                                                      2.84˜3.02(2H, m), 3.59(2H,                                              s), 4.09(3H, s),                                                              6.72˜6.88(2H,                                                           m), 7.20˜7.44(7H, m)  mol.                                              form.; C.sub.25 H.sub.32 N.sub.2                                              O.sub.2.HCl                           66                                                                                ##STR124##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10-2.10(11H, m),                                                            2.60˜3.00(4H, m), 3.45 (2H,                                             s), 3.45˜3.80(1H, m),                                                   3.86(6H, s), 6.22 (1H, bs),                                                   6.57(1H, s), 7.20(5H, s),                                                     7.46(1H, s) mol form.; C.sub.25                                               H.sub.32 N.sub.2 O.sub.3.HCl          67                                                                                ##STR125##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.08˜2.10(11H, m),                                                      2.50˜2.95(4H, m), 3.01 (3H,                                             s), 3.45(2H, s),                                                              3.45˜3.60(1H, m), 3.85 (6H,                                             s), 6.52(1H, s), 7.10(1H, s),                                                 7.20(5H, s) mol. form.; C.sub.26                                              H.sub.34 N.sub.2 O.sub.3.HCl          68                                                                                ##STR126##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.02˜2.12(9H, m),                                                       2.50˜3.05(4H, m), 3.43(2H,                                              s), 3.43˜3.85(1H, m),                                                   3.88(6H, s), 6.58(1H, s),                                                     6.50˜6.82(1H, m), 7.20(5H,                                              s), 7.46(1H, s) mol. form.;                                                   C.sub.24 H.sub.30 N.sub.2                                                     O.sub.3.NCl                           69                                                                                ##STR127##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.17(3H, t), 1.10˜2.15(9H,                                              m), 2.68(2H, q), 2.89(2H, bd),                                                3.14(2H, s), 3.51(2H, s),                                                     3.55(2H, s), 3.87(2H, bt),                                                    7.07˜7.35(9H, m) mol.                                                   form.; C.sub.25 H.sub.33 N.sub.3                                              O.2HCl                                __________________________________________________________________________

    TABLE 6      Ex.   No. Structural formula Physicochemical constant (m.p., elem.     anal., NMR, etc.)          70      ##STR128##      ##STR129##      71     ##STR130##      ##STR131##      72     ##STR132##      ##STR133##      73     ##STR134##      ##STR135##      74     ##STR136##      ##STR137##      75     ##STR138##      ##STR139##      76     ##STR140##      ##STR141##      77     ##STR142##      ##STR143##      78     ##STR144##      ##STR145##      79     ##STR146##      ##STR147##      80     ##STR148##      ##STR149##      81     ##STR150##      ##STR151##      82     ##STR152##      ##STR153##      83     ##STR154##      ##STR155##      84     ##STR156##      ##STR157##      85     ##STR158##      ##STR159##

                                      TABLE 7                                     __________________________________________________________________________    Ex.                                    Physicochemical constant               No.                                                                              Structural formula                  (m.p., elem. anal., NMR,               __________________________________________________________________________                                           etc.)                                  86                                                                                ##STR160##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              0.96˜2.24(9H, m), 1.25(3H,                                              t), 2.60˜3.08(2H, m),                                                   3.44(2H, s), 3.12˜3.15(4H,                                              m), 7.20 (5H, s), 8.44(2H, s)          87                                                                                ##STR161##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.00˜2.08(9H, m), 2.70(2H,                                              bd), 3.04(3H, bd), 3.40(2H, bd),                                              7.17(5H, s), 7.40˜7.61(2H,                                              m), 7.66˜7.82(2H, m),                                                   7.99˜8.11(2H, m), 7.83 (1H,                                             d) mol. form.; C.sub.25 H.sub.29                                              N.sub.3 O.2HCl                         88                                                                                ##STR162##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.1(9H, m),                                                         2.7˜3.0(2H, m), 3.50(2H, s),                                            .90(2H, t), 6.9˜7.6(12H, m),                                            8.03(2H, d) mol. form.; C.sub.27                                              H.sub.29 N.sub.3 O.sub.3.HCl           89                                                                                ##STR163##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.1(9H, m),                                                         2.7˜3.0(2H, m), 3.48(2H, s),                                            .8˜4.0(2H, m),                                                          6.6˜7.4(14H, m) mol. form.;                                             C.sub.27 H.sub.29 N.sub.2 OF.HCl       90                                                                                ##STR164##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.2(9H, m),                                                         2.7˜3.0(2H, m), 3.48(2H, s),                                            .89(2H, m), 6.8˜7.4(15H, m)                                             mol. form.; C.sub.27 H.sub.30                                                 N.sub.2 O.HCl                          91                                                                                ##STR165##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.16(3H, t), 1.1˜2.2(9H, m),                                            2.7˜3.0(2H,                                                             m), 3.1˜3.4(4H, m), 3.52(2H,                                            s), 6.5˜7.4(10H, m) mol.                                                form.; C.sub.22 H.sub.30 N.sub.2       92                                                                                ##STR166##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.10˜2.06(9H, m), 2.82(2H,                                              bd), 3.43(2H, s), 3.58(3H, s),                                                3.88(2H, bt), 6.50(2H, d),                                                    6.69(2H, d), 6.98(5H, bs),                                                    7.19(5H, s) mol. form.; C.sub.28                                              H.sub.32 N.sub.2 O.sub.2               93                                                                                ##STR167##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.78(3H, s), 1.0˜2.1(9H, m),                                            2.6˜3.0(2H, m), 3.43(2H, s),                                            3.75(2H, m), 3.73(3H, s), 6.64(4H,                                            dd), 7.26(5H, s) mol. form.;                                                  C.sub.23 H.sub.30 N.sub.2 O.sub.2.H                                           Cl                                     94                                                                                ##STR168##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.1(9H, m), 1.84(3H, s),                                            2.7˜3.0(2H, m), 3.44(2H, s),                                            3.5˜3.8(2H, m), 3.80(3H, s),                                            .5˜6.9(3H, m), 7.22(6H, s)                                              mol. form.; C.sub.23 H.sub.30                                                 N.sub.2 O.sub.2                        95                                                                                ##STR169##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.16˜2.16(9H, m),                                                       2.68˜2.98(2H, m), 3.49(2H,                                              s), 3.84˜4.09(2H, t),                                                   6.91˜7.40 (10H, m),                                                     8.22˜8.44(2H, m), 8.62(1H,                                              s)                                     96                                                                                ##STR170##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.98˜2.26(20H, m), 2.85(2H,                                             bd), 3.48(2H, s) 3.62(2H, bt),                                                6.96˜7.40(9H, m) mol. form.;                                            C.sub.27 H.sub.36 N.sub.2 O.HCl        97                                                                                ##STR171##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              0.90˜2.10(9H, m),                                                       2.65˜2.98(2H, m), 2.83 (3H,                                             s), 3.47(2H, s),                                                              3.52˜3.92(2H, m), 7.26(5H,                                              s), 7.26˜7.43(5H, m) mol.                                               form.; C.sub.21 H.sub.20 N.sub.2                                              O.sub.2 S.HCl                          98                                                                                ##STR172##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.02(3H, t), 1.10˜2.00(9H,                                              m), 1.98(2H, q), 2.80(2H, bd),                                                3.43(2H, s), 3.55˜3.80(2H,                                              m), 6.97˜7.40(5H, m),                                                   7.20(5H, s) mol. form.; C.sub.23                                              H.sub.30 N.sub.2 O.HCl                 99                                                                                ##STR173##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.0˜2.1(9H, m), 2.18(6H, s),                                            2.6˜3.0(4H, m), 3.38(2H, s),                                            3.4˜3.8(2H, m),                                                         6.9˜7.5(10H, m) mol. form.;                                             C.sub.24 H.sub.33 N.sub.3 O.2HCl       100                                                                               ##STR174##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.17(3H, t), 1.1˜2.1(9H, m),                                            2.6˜2.9(2H, m), 3.40(2H, s),                                            3.4˜3.8(2H, m), 4.08(2H, t),                                            .19(10H, s) mol. form.; C.sub.23                                              H.sub.30 N.sub.2 O.sub.2.HCl           101                                                                               ##STR175##                          .sup.1 H-NMR(CDCl.sub.3)δ;                                             1.24˜1.81(9H, m), 2.0(3H,                                               s), 2.82˜2.96 (2H, d),                                                  3.54(2H, s), 3.80(2H, m), 7.18                                                (2H, dd), 7.36(5H, s), 8.70(2H,                                               dd) mol. form.; C.sub.21 H.sub.27                                             N.sub.3 O                              102                                                                               ##STR176##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.83(3H, s), 1.0˜2.2(9H, m),                                            2.6˜3.0(2H, m), 3.43(2H, s),                                            3.66(3H, t), 6.8˜7.4(9H, m)                                             mol. form.; C.sub.22 H.sub.27                                                 N.sub.2 OCl.HCl                        103                                                                               ##STR177##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.16˜2.06(9H, m), 2.83(2H,                                              bd), 3.47(2H, s), 3.78(2H, bt),                                               5.42(1H, dd), 5.90(1H, dd),                                                   6.20(1H, dd), 6.99˜7.40(10H,                                            m) mol. form.; C.sub.23 H.sub.28                                              N.sub.2 O.HCl                          104                                                                               ##STR178##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.14˜2.03(12H, m), 2.83(2H,                                             bd), 3.44(2H, s), 3.64(2H, bt),                                               7.00(2H, s), 7.08(2H, s), 7.22(5H,                                            s) mol. form.; C.sub.22 H.sub.27                                              FN.sub.2 O.HCl                         105                                                                               ##STR179##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.15˜1.95(12H, m), 2.84(2H,                                             bd), 3.65(2H, s), 3.67(2H, bt),                                               6.75˜7.07(3H, m), 7.23(6H,                                              s) mol. form.; C.sub.22 H.sub.27                                              FN.sub.2 O.HCl                         106                                                                               ##STR180##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.0˜2.1(9H, m),                                                         2.6˜3.0(2H, m), 3.43(2H, s),                                            .85(2H, m), 6.4˜6.7(3H, m),                                             6.9˜7.3(8H, m),  8.34(2H, d)                                            ol. form.; C.sub.27 H.sub.31                                                  N.sub.3 O.sub.2.2HCl                   107                                                                               ##STR181##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.0˜2.1(9H, m),                                                         2.6˜3.0(2H, m), 3.41(2H, s),                                            .84(2H, m), 6.6˜7.2(5H, m),                                             7.22(5H, s), 8.37(2H, d) mol.                                                 form.; C.sub.26 H.sub.28 N.sub.3                                              OF.2HCl                                108                                                                               ##STR182##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.0˜2.1(9H, m),                                                         2.6˜3.0(2H, m), 3.43(2H, s),                                            .57(6H, s), 3.83(2H, m),                                                      6.0˜6.2(3H,                                                             m), 7.0˜7.4(7H, m), 8.35(2H,                                            d)                                     109                                                                               ##STR183##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.77(3H, s), 1.0˜2.1(9H, m),                                            2.32(3H, s), 2.6˜2.9(2H, m),                                            3.40(2H, s), 3.63(2H,                                                         m), 6.7˜7.3(9H, m) mol.                                                 form.; C.sub.28 H.sub.33 N.sub.3                                              O.sub.3.HCl                            110                                                                               ##STR184##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.85(3H, s), 1.1˜2.2(9H, m),                                            2.6˜3.0(2H, m), 3.42(2H, s),                                            3.60(2H, m), 3.75(6H, s), 6.20                                                (2H, d), 6.35(1H, m), 7.18(5H, s)                                             mol. form.; C.sub.24 H.sub.32                                                 N.sub.2 O.sub.3.HCl                    111                                                                               ##STR185##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.1(9H, m),                                                         2.6˜3.0(2H, m), 3.50(2H, s),                                            .83(2H, m), 6.58(4H, dd), 7.04(2H,                                            d), 7.19(5H, s), 8.28(2H, d) mol.                                             form.; C.sub.26 H.sub.29 N.sub.3                                              O.sub.2.2HCl                           112                                                                               ##STR186##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.07˜2.35(9H, m), 2.99(2H,                                              bd), 3.62(2H, s), 3.81(2H, bt),                                               6.31˜6.56(3H, m),                                                       6.84˜7.11 (3H, m), 7.25(5H,                                             s), 8.31(2H, bs) mol. form.;                                                  C.sub.26 H.sub.29 N.sub.3 O.sub.2.2                                           HCl                                    113                                                                               ##STR187##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              1.1˜2.1(9H, m),                                                         2.6˜3.0(2H, m), 3.44(2H, s),                                            .68(3H, m), 3.85(2H, m), 6.78(4H,                                             dd), 7.02(2H, d), 7.23(5H, s),                                                8.37(2H, d) mol. form.; C.sub.27                                              H.sub.31 N.sub.3 O.sub.2 .2HCl         114                                                                               ##STR188##                         .sup.1 H-NMR(CDCl.sub.3)δ;                                              7.20(11H, m), 8.05(1H, m),                                                    1.2˜1.83(9H,                                                            m), 2.65˜2.81(2H, d),                                                   3.4(2H, s), 3.90(2H,                                                          m), 6.20˜6.52(2H, m) mol.                                               form.; C.sub.25 H.sub.29 N.sub.3.2H                                           Cl                                     __________________________________________________________________________

    TABLE 8        Physicochemical constant Ex. No. Structural formula (m.p., elem.     anal., NMR, etc.)          115      ##STR189##      .sup.1      H-NMR(CDCl.sub.3)δ;0.80˜2.12(12H, m), 2.52˜3.64(8H,     m),7.06˜7.52(10H, m)      116     ##STR190##      .sup.1      H-NMR(CDCl.sub.3)δ;1.08˜2.10(9H, m), 2.80˜2.92(2H,     d), 3.00(3H, s), 3.34˜3.50(4H, m), 3.90(2H, s),6.60(2H, d),     7.21˜7.28(7H, m)mol. form.; C.sub.22 H.sub.29 N.sub.3 O.2HCl  117      ##STR191##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.1(9H, m), 2.31(3H, s),     2.5˜3.1(5H, m),3.1˜3.6(4H, m), 7.0˜7.4(9H, m)mol.     form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      118     ##STR192##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.2(9H, m), 2.7˜3.0(2H,     m), 3.29(2H, m),3.50(2H, s), 3.81(2H, s), 5.8(1H, s), 7.25(5H, s),     7.3˜7.7(3H, m), 8.03(1H, d)mol. form.; C.sub.22 H.sub.27 N.sub.3     O.sub.3.HCl      119     ##STR193##      .sup.1 H-NMR(CDCl.sub.3)δ; (in free form)1.10˜2.06(17H, m),     2.10˜2.32(3H, m), 2.96(3H, s), 3.20˜3.52(4H, m), 4.08˜4     .16(2H, d),7.36˜7.76(5H, m)mol. form.; C.sub.22 H.sub.34 N.sub.2     O.HCl      120     ##STR194##      .sup.1      H-NMR(CDCl.sub.3)δ;1.20˜2.08(9H, m), 2.80˜2.92(2H,     d), 3.12(3H, s), 3.46˜3.64(4H, m), 6.42(1H, dd),7.00(1H, dd),     7.26˜7.45(6H, m)mol. form.; C.sub.20 H.sub.26 N.sub.2 O.sub.2.HCl     121      ##STR195##      .sup.1      H-NMR(CDCl.sub.3)δ;1.02˜2.06(9H, m), 2.71˜3.57(9H,    6     m),.16˜6.54(2H, m), 7.10˜7.55(10H, m)mol. form.; C.sub.24     H.sub.30 N.sub.2 O.HCl      122     ##STR196##      .sup.1      H-NMR(CDCl.sub.3)δ;1.1˜ 2.1(7H, m), 2.8˜3.05(2H, m),     3.05˜3.15(2H, m), 3.49(2H, s), 5.1(1H, ), 7.0˜7.5(10H,     m)mol. form.; C.sub.20 H.sub.24 N.sub.2 O.sub.2.HCl      123     ##STR197##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜3.08(20H, m), 7.22(5H, bs),     7.37(5H, s)mol. form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      124     ##STR198##      .sup.1 H-NMR(CDCl.sub.3)δ;1.30˜2.24(9H, m), 2.86(2H, bd),     3.32˜3.60(4H, m), 6.08˜6.28(2H, m), 7.20˜8.02(6H,     m)mol. form.; C.sub.19 H.sub.24 N.sub.2 O.sub.2.HCl      125     ##STR199##       .sup.1      H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.8˜3.1(2H, m),     3.50(4H, s),7.30(10H, s)mol. form.; C.sub.20 H.sub.23 NO.sub.3.HCl  126      ##STR200##      .sup.1 H-NMR(CDCl.sub.3)δ; (in free form)1.20˜2.16(9H, m),     2.64˜3.0(2H, bd), 3.46(2H, s), 3.36˜3.60(2H, m), 3.80(6H,     s), 5.60(1H, bs), 6.50˜6.60(2H, d), 7.16˜7.40(6H, m)moo.     form.; C.sub.23 H.sub.30 N.sub.2 O.sub.3.HCl      127     ##STR201##      .sup.1 H-NMR(CDCl.sub.3)δ; (in free form)1.12˜2.16(9H, m),     2.76˜3.0(2H, bd), 3.48(2H, s), 3.32˜3.60(2H, m), 3.92(3H,    6     s),.32˜7.40(8H, m), 8.26(1H, bs), 14.0(1H, s)mol. form.; C.sub.22     H.sub.28 N.sub. 2 O.sub.3.HCl      128     ##STR202##      .sup.1 H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.7˜3.0(2H,     m), 3.1˜3.4(2H,m), 3.46(2H, s), 4.90(1H), 6.9˜7.4(10H,     m)mol. form.; C.sub.21 H.sub.26 N.sub.2 O.sub.2.HCl      129     ##STR203##      .sup.1 H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.7˜3.0(4H,     m), 3.1˜3.6(2H, m), 3.55(2H, s), 5.5(1H), 7.30(10H, s)mol. form.;     C.sub.22 H.sub.28 N.sub.2 O.HCl      130     ##STR204##      .sup.1 H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.7˜3.0(2H,     m), 3.2˜3.4(2H, m), 3.40(2H, s), 5.9(1H), 6.39(1H, d),7.1˜7.8     (11H, m) mol. form.; C.sub.23 H.sub.28 N.sub.2 O.HCl      131     ##STR205##      .sup.1 H-NMR(CDCl.sub.3)δ; (in free form)1.1˜2.2(9H, m),     2.6˜3.0(2H, bd), 3.44(2H, s),3.36˜3.6(2H, m), 3.90(3H, s),     6.9˜8.30(10H, m)mol. form.; C.sub.22 H.sub.20 N.sub.2 O.sub.2.HCl     132      ##STR206##      .sup.1 H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.3˜2.7(4H,     m), 2.7˜3.0(2H,m), 3.0˜3.5(4H, m), 6.1(1H), 7.0˜7.7(10H     , m)mol. form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      133     ##STR207##      .sup.1 H-NMR(CDCl.sub.3)δ;1.17(3H, t), 1.2˜ 2.1(9H, m),     2.17(2H, q),2.7˜3.0(2H, m), 3.1˜3.4(2H, m), 3.45(2H,     s),5.3(1H), 7.21(5H, s)mol. form., C.sub.17 H.sub.26 N.sub.2 O.HCl  134      ##STR208##      .sup.1      H-NMR(CDCl.sub.3)δ;1.1˜2.0(12H, m), 2.6˜3.0(2H, m),     3.0˜3.3(2H, m), 3.41(2H, s), 3.3˜3.4(1H, m), 7.23(10H,     s)mol. form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      135     ##STR209##      .sup.1 H-NMR(CDCl.sub.3)δ;0.90˜2.10(9H, m), 2.78(2H, bd),     3.00˜3.70(2H, m), 3.43(2H, s), 4.40˜4.85(2H, m),7.27(10H,     s), 7.38(5H, s)mol. form.; C.sub.28 H.sub.32 N.sub.2 O.HCl      136     ##STR210##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.1(9H, m), 2.7˜3.0(2H,     m), 3.48(2H, s),4.36(2H, t), 7.0˜7.7(8H, m), 7.8˜8.2(2H,     m)mol. form.; C.sub.21 H.sub.25 NO.sub.2      137     ##STR211##      .sup.1      H-NMR(CDCl.sub.3)δ;0.86˜1.90(9H, m), 2.56˜3.05(4H,     m), 3.38(2H, d), 4.56(1H, s), 4.68(1H, s), 7.00˜7.56(12H, m),     8.10(2H, m)mol. form.; C.sub.28 H.sub.31 N.sub.3 O.sub.3.HCl  138      ##STR212##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.1(9H, m), 2.7˜3.0(2H,     m), 3.1˜3.4(2H, m), 3.47(2H, s), 5.58(1H, dd), 5.9˜6.1(2H,     m), 7.29(5H, s)mol. form.; C.sub.17 H.sub.24 N.sub.2 O.HCl      139     ##STR213##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜4.08(16H, m), 7.38(10H,     s)mol. form.; C.sub.22 H.sub.26 N.sub.2 O.sub.2      140     ##STR214##      .sup.1      H-NMR(CDCl.sub.3)δ;0.90˜2.10(9H, m), 2.55˜3.50(7H,    3     m),.52(2H, s), 7.38(5H, s), 7.80(4H, ABq)mol. form.; C.sub.22 H.sub.27     N.sub.3 O.sub.3.HCl      141     ##STR215##      .sup.1      H-NMR(CDCl.sub.3)δ;0.96˜2.08(3H, m), 2.60˜3.10(6H,    3     m),.48(2H, d), 7.16˜7.92(14H, m)      142     ##STR216##      .sup.1      H-NMR(CDCl.sub.3)δ;0.80˜2.04(9H, m), 2.48˜2.88(2H,    3     m),.12˜3.52(4H, m) 7.03˜7.72(14H, m)      143     ##STR217##      .sup.1 H-NMR(CDCl.sub.3)δ;1.01˜2.01(19H, m), 2.33(3H, s),     2.63˜3.04(5H, bd), 3.42(2H, bd), 7.15(4H, bs),7.35(5H, s)mol.     form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      144     ##STR218##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜1.96(11H, m), 2.30(3H, s),     3.38(2H, bd),7.02(4H, bd), 7.28(5H, s)mol. form.; C.sub.23 H.sub.30     N.sub.2 O      145     ##STR219##      .sup.1      H-NMR(CDCl.sub.3)δ;0.90˜2.18(9H, m), 2.52˜3.70(7H,     m), 3.72(2H, s), 7.10˜7.88(4H, m), 7.38(5H, s)mol. form.; C.sub.22     H.sub.27 N.sub.3 O.sub.3      146     ##STR220##      ##STR221##      147     ##STR222##      .sup.1 H-NMR(CDCl.sub.3)δ;0.82(9H, s), 1.02˜2.28(9H, m),     2.60˜3.60(9H, m), 7.28(5H, s)mol. form.; C.sub.20 H.sub.32 N.sub.2     O.HCl      148     ##STR223##      .sup.1 H-NMR(CDCl.sub.3)δ;0.85(9H, s), 1.12˜2.28(9H, m),     2.76(2H, bd),3.42(2H, q), 7.38(3H, m), 7.67(2H, dd)mol. form.; C.sub.19     H.sub.30 N.sub.2 O.HCl      149     ##STR224##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.2(9H, m), 1.6˜2.1(5H,     m), 2.2˜2.6(4H, m), 6.8˜7.7(9H, m)mol. form.; C.sub.22     H.sub.27 N.sub.2 O.HCl      150     ##STR225##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.05(9H, m), 2.08,2.12(total     3H, eachs), 2.82(2H, bd), 3.03˜3.43(2H, m), 3.44(2H, s), 4.47,4.56(     total 3H, each s), 7.35(10H, s)mol. form.; C.sub.23 H.sub.30 N.sub.2     O.HCl      151     ##STR226##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.08(9H, m), 2.78(2H, bd),     2.88(3H, s),3.10˜3.45(2H, m), 3.43(2H, s), 3.57(2H, s),7.22(10H,   m     s)ol. form.; C.sub.23 H.sub.30 N.sub.2 O.HCl      152     ##STR227##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.00(9H, m), 2.03(3H, s),     2.80(2H, bd),2.88,2.91(total 3H, each s), 3.05˜3.40(2H, m),     3.43(3H, s), 7.20(5H, s)mol. form.; C.sub.17 H.sub.26 N.sub.2 O.HCl  153      ##STR228##      .sup.1 H-NMR(CDCl.sub.3)δ;1.1˜2.2(9H, m), 2.6˜3.2(5H,     m), 3.2˜3.6(4H, m), 6.8˜7.1(1H, m), 7.3(5H, s),7.5˜7.8(     3H, m), 8.24(2H, d)mol. form.; C.sub.26 H.sub.29 N.sub.3 O.sub.3.HCl     154      ##STR229##      .sup.1      H-NMR(CDCl.sub.3)δ;1.00˜2.08(10H, m), 2.72˜3.08(5H,     m),3.33(2H, bd), 6.16(1H, bs), 7.07(7H, bs)mol. form.; C.sub.20 H.sub.26     N.sub.2 O.sub.2.HCl      155     ##STR230##      .sup.1      H-NMR(CDCl.sub.3)δ;0.15(2H, m), 0.56(2H, m), 0.90˜2.23(10H,     m),3.00(5H, m), 3.34(4H, m), 7.40(5H, s)mol. form.; C.sub.19 H.sub.28     N.sub.2 O.HCl      156     ##STR231##      .sup.1      H-NMR(CDCl.sub.3)δ;1.00˜2.02(9H, m), 2.64˜3.00(5H,     m), 3.41(4H, m), 7.15(1H, m), 7.27(5H, s),7.50(1H, d), 8.41(2H, m)mol.     form.; C.sub.21 H.sub.27 N.sub.3 O.HCl      157     ##STR232##      .sup.1      H-NMR(CDCl.sub.3)δ;1.04˜1.04(11H, m), 2.64˜3.00(5H,     m), 3.58(2H, s), 7.01(1H, m), 7.27(5H, s), 7.58(2H, m), 8.44(1H, d)mol.     form.; C.sub.21 H.sub.27 N.sub.3 O.HCl      158     ##STR233##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.00(4H, m), 2.83(2H, bd),     3.24(2H, bd),3.45(2H, s), 3.59(2H, s), 5.85(1H, bs),7.27(5H, s),     7.77(4H, ABq)mol. form.; C.sub.22 H.sub.27 N.sub.3 O.sub.3.HCl  159      ##STR234##      .sup.1 H-NMR(CDCl.sub.3)δ;1.0˜2.1(9H, m), 2.6˜3.2(5H,     m), 3.2˜3.7(4H, m), 7.25(5H, s), 7.3˜8.1(7H, m)mol. form.;     C.sub.26 H.sub.30 N.sub.2 O.HCl      160     ##STR235##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.10(9H, m), 2.25(3H, s),     2.81(2H, bd),2.97(3H, bs), 3.10˜ 3.45(2H, m), 3.43(2H, s),7.23(4H,     ABq), 7.27(5H, s)mol. form.; C.sub.24 H.sub.30 N.sub.2 O.sub.3.HCl  161      ##STR236##      .sup.1      H-NMR(CDCl.sub.3)δ;1.06˜1.92(9H, m),2.70˜2.99(5H,     m),3.44(2H, s),7.22(2H, d),7.38(5H, s),8.50(2H, d)mol. form.; C.sub.21     H.sub.27 N.sub.3 O.2HCl      162     ##STR237##      .sup.1 H-NMR(CDCl.sub.3)δ;0.90˜1.05(9H, m), 2.70(3H, s),     3.00(2H, d),3.22(2H, s), 3.37(1H, s), 3.46(1H, s),7.18˜7.60(9H,     m), 7.78(3H, m)mol. form.; C.sub.26 H.sub.30 N.sub.2 O.HCl      163     ##STR238##       .sup.1      H-NMR(CDCl.sub.3)δ;0.7˜2.2(20H, m), 2.8˜3.2(4H, ),     3.55(2H, m),6.95(1H, s), 8.02(2H, d), 8.34(2H, d)mol. form.; C.sub.21     H.sub.31 N.sub.3 O.sub.2      164     ##STR239##      .sup.1      H-NMR(CDCl.sub.3)δ;1.1˜2.1(12H, m), 2.7˜3.1(5H, m),     3.2˜3.6(4H, m), 4.22(2H, q), 6.7(1H, m), 7.2˜7.4(6H, m)mol.     form.; C.sub.21 H.sub.30 N.sub.2 O.sub.3.HCl      165     ##STR240##      .sup.1      H-NMR(CDCl.sub.3)δ;0.56˜3.36(23H, m), 3.40˜3.68(2H,     m),4.28(2H, s), 7.18(5H, s), 8.34(2H, d),8.58(2H, d)      166     ##STR241##      .sup.1 H-NMR(CDCl.sub.3)δ;1.16˜2.12(9H, m), 2.89(2H, bd),     3.47(2H, s),4.35(2H, bt), 7.08˜7.74(11H, m), 8.08(1H,bd), 8.23(1H,     dd)      167     ##STR242##      .sup.1      H-NMR(CDCl.sub.3)δ;1.08˜1.94(9H, m), 2.68˜3.02(7H,     m), 3.40(2H, d), 7.27(5H, s), 7.41(2H, d), 7.78(2H, d),10.0(1H, s)mol.     form.; C.sub.23 H.sub.28 N.sub.2 O.sub.2.HCl      168     ##STR243##      .sup.1      H-NMR(CDCl.sub.3)δ;1.10˜1.98(15H, m), 2.77˜2.98(6H,     m),3.12˜3.46(4H, m), 7.26(9H, m)mol. form.; C.sub.25 H.sub.34     N.sub.2 O.HCl       169     ##STR244##      .sup.1      H-NMR(CDCl.sub.3)δ;1.00˜2.00(9H, m), 2.60˜3.00(7H,     m), 3.45(2H, m), 6.95(2H, d), 7.26(5H, s), 7.90(2H, d)mol. form.;     C.sub.23 H.sub.27 N.sub.2 OF.sub.3.HCl      170     ##STR245##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.10(3H, m), 2.87(2H, bd),     2.99(3H, s),3.10˜3.50(2H, m), 3.48(3H, s), 6.35˜7.35(5H, m),     7.83(5H, s)mol. form.; C.sub.22 H.sub.28 N.sub.2 O.sub.2.HCl  171      ##STR246##      .sup.1 H-NMR(CDCl.sub.3)δ;1.10˜ 1.88(12H, m), 2.80(2H, d),     2.98(3H, s),3.23˜3.44(4H, m), 4.02(2H, m), 6.84(2H, d),7.26(7H,     m)mol. form.; C.sub.24 H.sub.32 N.sub.2 O.sub.2.HCl      172     ##STR247##      .sup.1 H-NMR(CDCl.sub.3)δ;1.00˜2.08(9H, m),2.83(2H,     bd),2.98(3H, s),3.12˜3.50(2H, m), 3.47(2H, s), 5.08(2H, s),7.15(4H,      ABq), 7.38(5H, s), 7.96(2H, ABq)      173     ##STR248##      .sup.1      H-NMR(CDCl.sub.3)δ;1.04˜1.98(7H, m), 2.20˜3.80(7H,    6     m),.60˜7.34(7H, m), 8.67(2H, d)      174     ##STR249##      .sup.1      H-NMR(CDCl.sub.3)δ;0.90˜2.20(11H, m), 2.60˜3.30(2H,     m), 2.85,3.03(total 3H, each bs), 3.48, 3.55(total2H, each bs), 3.88(3H,     s), 7.19, 7.21(total5H, each s), 7.67(4H, ABq)mol. form.; C.sub.24     H.sub.30 N.sub.2 O.sub.2.HCl      175     ##STR250##      .sup.1      H-NMR(CDCl.sub.3)δ;0.90˜2.06(9H, s), 2.70˜3.02(10H,     m), 3.20˜3.62(4H, m), 4.50(2H, s), 7.21˜7.30(9H, d)mol.     form.; C.sub.25 H.sub.34 N.sub.2 O.sub.2.HCl      176     ##STR251##      .sup.1 N-NMR(CDCl.sub.3)δ;9.90˜2.10(9H, m), 2.81(2H, bd),     3.45(2H, s),4.11(2H, t), 6.98˜7.82(8H, m), 7.21(5H, s)mol. form.;     C.sub.27 H.sub.28 N.sub.2 O.sub.2.HCl      177     ##STR252##      .sup.1      H-NMR(CDCl.sub.3)δ;1.29(3H, s), 1.40(3H, s), 1.40˜2.20(9H,     m),2.83(2H, bd), 3.00(3H, s), 3.20˜3.50(2H, m),3.48(2H, s),     4.56(1H, quirtet), 7.08(4H, ABq), 7.28(5H, s)mol. form.; C.sub.25     H.sub.34 N.sub.2      O.sub.2.HCl

EXAMPLE 1781-Benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine ##STR253##

0.85 g of 5,6-dimethoxy-1-indanone and 1.38 g of1-benzoyl-4-piperidinecarbaldehyde were dissolved in 20 ml of anhydrousTHF to obtain a solution. 1.02 g of 28% sodium methylate was added tothe solution at 0° C. The obtained mixture was stirred at a roomtemperature for 2 hours, diluted with ethyl acetate, washed with asaturated aqueous solution of common salt, dried over magnesium sulfateand concentrated in a vacuum. The obtained residue was purified througha silica gel column to obtain 1.23 g of1-benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine(yield: 71%).

1.23 g of this compound was dissolved in 20 ml of THF, followed by theaddition of 0.3 g of 10% palladium/carbon. After the hydrogenation hadbeen carried out at a room temperature under an ordinary pressure forone day, the catalyst was filtered out and the filtrate was concentratedin a vacuum. The residue was recrystallized from methylenechloride/hexane to obtain 1.10 g of the title compound (yield: 89%). Thecharacteristics thereof are as follows:

m.p. (° C.): 151 to 152.

elemental analysis as C₂₄ H₂₇ NO₄.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             73.26       6.92   3.56                                          found (%)    73.30       6.85   3.32                                          ______________________________________                                    

EXAMPLE 179 4-[(5,6-Dimethoxy-1-indanon)-2-yl]methylpiperidinehydrochloride ##STR254##

9.00 g of 1-benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidinewas dissolved in 90 ml of dioxane, followed by the addition of 90 ml of6 N hydrochloric acid. The obtained mixture was heated under reflux for10 hours and concentrated in a vacuum. The residue was diluted withwater and extracted with ethyl acetate. The pH of the aqueous layer wasadjusted to 12 with a 50% aqueous solution of sodium hydroxide andextracted with methylene chloride. The organic layer was washed with asaturated aqueous solution of common salts, dried over magnesium sulfateand concentrated in a vacuum. The obtained residue was converted intoits hydrochloride by an ordinary method. The obtained product wasrecrystallized from methanol/ethanol to obtain 6.30 g of the titlecompound (yield: 85%). The characteristics thereof are as follows:

m.p. (° C.): 249 to 250 (dec.).

elemental analysis as C₁₇ H₂₃ NO₃.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             62.67       7.42   4.30                                          found (%)    62.75       7.31   4.52                                          ______________________________________                                    

EXAMPLE 1801-(3-Fluorobenzyl)-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidinehydrochloride ##STR255##

0.25 g of 4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine wasdissolved in 6 ml of THF, followed by the addition of 0.29 ml oftriethylamine and 0.13 ml of 3-fluorobenzyl bromide. The obtainedmixture was heated under reflux for 2 hours and concentrated in avacuum. The residue was diluted with ethyl acetate, washed with a 10%aqueous solution of sodium carbonate and a saturated aqueous solution ofcommon salt successively, dried over magnesium sulfate and concentratedin a vacuum. The obtained residue was purified through a silica gelcolumn and converted into its hydrochloride by an ordinary method. Theobtained product was recrystallized from methylene chloride/IPE toobtain 0.27 g of the title compound (yield: 72%). The characteristicsthereof are as follows:

m.p. (° C.): 230 to 232 (dec.).

elemental analysis as C₂₄ H₂₈ NO₃.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             66.43       6.74   3.23                                          found (%)    66.18       6.79   3.11                                          ______________________________________                                    

EXAMPLE 181 1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidinedihydrochloride ##STR256##

1.00 g of 5,6-dimethoxy-1-indanone, 0.31 g of paraformaldehyde and 0.90ml of 1-benzylpiperazine were suspended in a mixture comprising 30 ml ofethanol and 2 ml of water. The pH of the obtained suspension wasadjusted to 3 with concentrated hydrochloric acid, heated under refluxfor 3 hours, cooled by allowing to stand and filtered to obtain a whitesolid. This solid was suspended in methylene chloride, washed with a 10%aqueous solution of sodium carbonate and a saturated aqueous solution ofcommon salt successively, dried over magnesium sulfate and concentratedin a vacuum. The obtained residue was purified through a silica gelcolumn and converted into its hydrochloride by an ordinary method. Theproduct was recrystallized from methanol to obtain 0.55 g of the titlecompound (yield: 23%). The characteristics thereof are as follows:

m.p. (° C.) 227 to 228 (dec.).

elemental analysis as C₂₃ H₂₉ N₂ O₃.2HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             60.79       6.88   6.16                                          found (%)    60.31       6.95   6.06                                          ______________________________________                                    

EXAMPLE 1824-[(5,6-Dimethoxy-1-indanon)-2-yl]methyl-1-ethoxycarbonylpiperidine##STR257##

0.50 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidinewas dissolved in 8 ml of benzene, followed by the addition of 0.15 ml ofethyl chloroformate. The obtained mixture was heated under reflux for 3hours, diluted with ethyl acetate, washed with a saturated aqueoussolution of sodium bicarbonate and a saturated aqueous solution ofcommon salt successively, dried over magnesium sulfate and concentratedin a vacuum. The obtained residue was recrystallized from ethylacetate/hexane to obtain 0.45 g of the title compound (yield: 94%). Thecharacteristics thereof are as follows:

m.p. (° C.): 132 to 133.

elemental analysis as C₂₀ H₂₇ NO₅.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             66.46       7.53   3.88                                          found (%)    66.79       7.53   4.00                                          ______________________________________                                    

EXAMPLE 1834-[(5,6-Dimethoxy-1-indenon)-2-yl]methyl-1-ethoxycarbonylpiperidine##STR258##

2.00 g of4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl-1-ethoxycarbonylpiperidine wasdissolved in 30 ml of carbon tetrachloride, followed by the addition of0.98 g of N-bromosuccinimide and 0.02 g of benzoyl peroxide. Theobtained mixture was heated under reflux for 5 hours, diluted withcarbon tetrachloride, washed with a saturated aqueous solution of sodiumbicarbonate and a saturated aqueous solution of common saltsuccessively, dried over magnesium sulfate and concentrated in a vacuum.

The obtained residue was dissolved in 20 ml of THF, followed by theaddition of 1.66 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The obtainedmixture was heated under reflux for 30 minutes and concentrated in avacuum. The residue was diluted with ethyl acetate, washed with asaturated aqueous solution of common salt, dried over magnesium sulfateand concentrated in a vacuum. The obtained residue was purified througha silica gel column to obtain 1.12 g of the title compound as an oil(yield: 56%).

molecular formula: C₂₀ H₂₅ NO₅.

¹ H-NMR(CDCl₃)δ; 1.23(3H,t), 1.41˜2.90(11H,m), 3.84(3H,S), 3.88(3H,S),4.10(2H,g), 6.60(1H,S), 6.97(1H,S), 7.03(1H,S).

EXAMPLE 184 1-Benzyl-4-[(1,3-indanedion)-2-ylidenyl]-methylpiperidine##STR259##

0.17 ml of diisopropylamine was added to 3 ml of anhydrous THF. 0.75 mlof a 1.6 M solution of n-butyllithium in hexane was added to theobtained mixture at 0° C. The obtained mixture was stirred at 0° C. for10 minutes and cooled to -78° C., followed by the addition of a solutionof 0.18 g of 1,3-indanedione in 8 ml of anhydrous THF and 0.21 ml ofhexamethylphosphoramide. The obtained mixture was stirred at -78° C. for15 minutes, followed by the addition of a solution of 0.35 g of1-benzyl-4-piperidinecarbaldehyde in 3 ml of anhydrous THF. The obtainedmixture was gradually heated to a room temperature, stirred at thattemperature overnight, diluted with methylene chloride, washed with asaturated aqueous solution of common salt, dried over magnesium sulfateand concentrated in a vacuum. The obtained residue was recrystallizedfrom methylene chloride/IPE to obtain 0.12 g of the title compound(yield: 29%). The characteristics thereof are as follows:

m.p. (° C.): 173 to 174 (dec.).

elemental analysis as C₂₂ H₂₁ NO₂.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             79.73       6.39   4.23                                          found (%)    79.43       6.20   4.31                                          ______________________________________                                    

EXAMPLE 185 1-Benzyl-4-[(5,6-dimethoxyinden)-2-yl]methylpiperidinehydrochloride ##STR260##

0.24 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanol)-2-yl]methylpiperidinewas dissolved in 5 ml of methylene chloride, followed by the addition ofa 10% solution of hydrochloric acid in ethyl acetate. The obtainedmixture was concentrated in a vacuum. The obtained residue wasrecrystallized form methylene chloride/IPE to obtain 0.24 g of the titlecompound (yield: 95%). The characteristics thereof are as follows:

m.p. (° C.): 216 to 217 (dec.).

elemental analysis as C₂₄ H₂₉ NO₂.HCl.

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        calculated (%)                                                                             72.07       7.56   3.50                                          found (%)    71.82       7.63   3.33                                          ______________________________________                                    

EXAMPLE 1861-Benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-ylidenyl[[propylpiperidinehydrochloride ##STR261##

0.31 ml of diisopropylamine was added to 5 ml of anhydrous THF. 1.39 mlof a 1.6 M solution of n-butyllithium in hexane was further added to theobtained mixture at 0° C. The obtained mixture was stirred at 0° C. for10 minutes and cooled to -78° C., followed by the addition of a solutionof 0.39 g of 5,6-dimethoxy-1-indanone in 5 ml of anhydrous THF and 0.35ml of hexamethylphosphoramide. The obtained mixture was stirred at -78°C. for 15 minutes, followed by the addition of a solution of 0.50 g of3-(1-benzyl-4-piperidine)propionaldehyde in 5 ml of anhydrous THF. Theobtained mixture was gradually heated to a room temperature, stirred atthat temperature for 3 hours, diluted with ethyl acetate, washed with asaturated aqueous solution of common salt, dried over magnesium sulfateand concentrated in a vacuum. The obtained residue was purified througha silica gel column and converted into its hydrochloride by an ordinarymethod of obtain 0.55 g of the title compound as an oil (yield: 61%).

molecular formula: C₂₆ H₃₁ NO₃.HCl.

¹ H-NMR(CDCl₃)δ; 1.10˜3.00(13H,m), 3.45(2H,S), 3.50(2H,S), 3.90(3H,S),3.95(3H,S), 6.58˜7.20(3H,m), 7.27(5H,S).

EXAMPLE 1871-Benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-yl]]-propylpiperidinehydrochloride ##STR262##

0.40 g of1-benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]]propylpiperidinewas dissolved in 15 ml of THF, followed by the addition of 0.1 g of 10%palladium/carbon. After the hydrogenation had been carried out at a roomtemperature under an ordinary pressure for 2 hours, the catalyst wasfiltered out and the filtrate was concentrated in a vacuum. The residuewas purified through a silica gel column and converted into itshydrochloride by an ordinary method to obtain 0.37 g of the titlecompound as an oil (yield: 84%).

molecular formula: C₂₆ H₃₃ NO₃.HCl.

¹ H-NMR(CDCl₃)δ; 1.00˜3.30(18H,m), 3.38, 3.43 (total 2H, each S),3.85(3H,S), 3.90(3H,S), 6.77, 6.83 (total 1H, each S), 7.05, 7.10 (total1H, each S), 7.18, 7.20 (total 5H, each S).

EXAMPLES 188 to 249

The compounds listed in Table 9 were each synthesized and analyzed.

                                      TABLE 9                                     __________________________________________________________________________    Ex-                                                                           am-                                        Physicochemical constants          ple                                                                              Structural formula                      (m.p., elemental analysis, NMR                                                etc.)                              __________________________________________________________________________    188                                                                               ##STR263##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.00˜3.40(14H, m),                                                    3.47(2H, S), 3.78(3H, S),                                                     6.90˜7.50(3H, m),                                                       7.23(5H, S). molecular                                                        formula: C.sub.23 H.sub.27                                                    NO.sub.2.HCl                       189                                                                               ##STR264##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.05˜2.12(9H, m),                                                     2.50˜3.40(5H, m),                                                       3.48(2H, S), 3.88(3H, S),                                                     6.98(1H, q), 7.15˜7.32(2H                                               , m), 7.23(5H, S), molecular                                                  formula: C.sub.23 H.sub.27                                                    NO.sub.2.HCl                       190                                                                               ##STR265##                             m.p. (°C.): 199 to 200                                                 (dec.) elemental analysis as                                                  C.sub.24 H.sub.29 NO.sub.3.HCl                                                 calculated (%)69.307.273.37                                                  found (%)69.247.403.38             191                                                                               ##STR266##                             m.p. (°C.): 198 to 199                                                 elemental analysis as C.sub.24                                                H.sub.29 NO.sub.3.HCl CHN                                                     calculated (%)69.307.273.37                                                   found (%)69.157.423.47             192                                                                               ##STR267##                             m.p. (°C.): 200 to 201                                                 elemental analysis as C.sub.25                                                H.sub.31 NO.sub.4.HCl CHN                                                     calculated (%)67.337.233.14                                                   found (%)67.107.163.00             193                                                                               ##STR268##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.05˜2.15(9H, m),                                                     2.55˜3.43(5H, m),                                                       3.48(2H, S), 7.23(5H, S),                                                     7.23˜7.43 (3H, m).                                                      molecular formula: C.sub.22                                                   H.sub.24 NOF.HCl                   194                                                                               ##STR269##                             m.p. (°C.): 175 to 177                                                 elemental analysis as C.sub.23                                                H.sub.27 NO.HCl CHN calculated                                                (%)74.687.633.79 found                                                        (%)72.77.643.62 1/2H.sub.2 O                                                  (%)72.907.713.70                   195                                                                               ##STR270##                             m.p. (°C.): 211 to 213                                                 (dec.) elemental analysis as                                                  C.sub.23 H.sub.27 NO.HCl CHN                                                  calculated (%)74.687.633.79                                                   found (%)72.687.493.70                                                        1/2H.sub.2 O (%)72.907.713.70      196                                                                               ##STR271##                             m.p. (°C.): 153 to 154                                                 elemental analysis as C.sub.23                                                H.sub.27 NO.sub.3 CHN calculate                                               d (%)75.597.453.83 found                                                      (%)75.777.283.64                   197                                                                               ##STR272##                             m.p. (°C.): 170 to 171                                                 (dec.) elemental analysis as                                                  C.sub. 23 H.sub.27 NO.sub.3                                                   CHN calculated                                                                (%)75.597.453.83 found                                                        (%)75.61.473.55                    198                                                                               ##STR273##                             m.p. (°C.): 175 to 176                                                 elemental analysis as C.sub.26                                                H.sub.33 NO.sub.3.HCl CHN                                                     calculated (%)70.337.723.15                                                   found (%)70.207.463.35             199                                                                               ##STR274##                             m.p. (°C.): 236 to 237                                                 (dec.) elemental analysis as                                                  C.sub.23 H.sub.25 NO.sub.3.HCl                                                 calculated (%)69.086.553.50                                                  found (%)68.976.823.29             200                                                                               ##STR275##                             m.p. (°C.): 195 to 196                                                 elemental analysis as C.sub.23                                                H.sub.27 NO.HCl CHN calculated                                                (%)74.687.633.79 found                                                        (%)74.72.773.78                    201                                                                               ##STR276##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜2.10(13H, m),                                                    2.60˜3.08(5H, m),                                                       3.41(2H, S),                                                                  7.00˜7.85(4H, m),                                                       7.19(5H, S). molecular                                                        formula: C.sub.24 H.sub.29                                                    NO.HCl                             202                                                                               ##STR277##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.17(3H, d),                                                                1.12˜2.10(9H, m),                                                       2.60˜2.93(2H, m),                                                       3.41(2H, S), 3.51(1H, q),                                                     7.20(5H, S), 7.30˜7.92                                                  (5H, m).  molecular formula:                                                  C.sub.22 H.sub.27 NO.HCl           203                                                                               ##STR278##                             m.p. (°C.): 126 to 127                                                 elemental analysis as C.sub.26                                                H.sub.33 NO.sub.3.HCl CHN                                                     calculated (%)70.337.723.15                                                   found (%)70.417.482.85             204                                                                               ##STR279##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.00˜3.40(20H, m),                                                    3.50(2H, S), 3.90(3H, S),                                                     3.97(3H, S), 6.88(1H, S),                                                     7.18(1H, S), 7.31(5H, S).                                                     molecular formula: C.sub.27                                                   H.sub.35 NO.sub.3.HCl              205                                                                               ##STR280##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.05˜3.36(22H, m),                                                    3.45(2H, S), 3.85(3H, S),                                                     3.90(3H, S), 6.78(1H, S),                                                     7.08(1H, S), 7.21(5H, S).                                                     molecular formula: C.sub.28                                                   H.sub.37 NO.sub.3.HCl              206                                                                               ##STR281##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜2.50(7H, m),                                                     2.70˜3.02(2H, m),                                                       3.48(2H, S), 3.56(2H, S),                                                     3.79(3H, S), 6.69(1H, dt),                                                    7.02˜7.50(3H, m),                                                       7.21(5H, m). molecular                                                        formula: C.sub.23 H.sub.25                                                    NO.sub.2.HCl                       207                                                                               ##STR282##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.50˜3.57(11H, m),                                                    3.48, 3.50(total 2H, each S),                                                 3.83, 3.85(total 3H, each S),                                                 6.57˜7.39(4H, m),                                                       7.22(5H, m). molecular                                                        formula: C.sub.23 H.sub.25                                                    NO.sub.2.HCl                       208                                                                               ##STR283##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.58˜2.55(7H, m),                                                     2.79˜3.02(2H, m),                                                       3.50(2H, S), 3.63(2H, d), 3.90                                                6H, S), 6.63(1H, dt), 6.93(1H,                                                d), 7.22(5H, S), 7.57(1H, d).                                                 molecular formula C.sub.24                                                    H.sub.27 NO.sub.3.HCl              209                                                                               ##STR284##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.50˜2.55(7H, m),                                                     2.78˜3.03(2H, m),                                                       3.48(2H, S), 3.56(2H, d),                                                     3.85(3H, S), 4.00(3H, S),                                                     6.62(1H, dt), 7.07(1H, d),                                                    7.21(1H, d), 7.22(5H, S).                                                     molecular formula: C.sub.24                                                   H.sub.27 NO.sub.3.HCl              210                                                                               ##STR285##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.50˜2.50(7H, m),                                                     2.78˜3.03(2H, m),                                                       3.48(2H, S), 3.53(2H, d),                                                     3.82(3H, S), 3.90(3H, S),                                                     4.03(3H, S), 6.58(1H, dt),                                                    6.61(1H, S), 7.25(5H, S).                                                     molecular formula: C.sub.25                                                   H.sub.29 NO.sub.4.HCl              211                                                                               ##STR286##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.52˜2.55(7H, m),                                                     2.78˜3.02(2H, m),                                                       3.50(2H, S), 3.59(2H, S),                                                     6.72(1H, dt), 7.05˜7.55(3                                               H, m), 7.22(5H, S). molecular                                                 formula: C.sub.22 H.sub.22                                                    NOF.HCl                            212                                                                               ##STR287##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.50˜2.55(7H, m),                                                     2.38(3H, S), 2.78˜3.02(2H                                               , m), 3.48(2H, S), 3.57(2H,                                                   S), 6.66(1H, dt),                                                             7.38˜7.60 (3H, m),                                                      7.21(5H, S). molecular                                                        formula: C.sub.23 H.sub.25                                                    NO.HCl                             213                                                                               ##STR288##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.48˜2.60(7H, m),                                                     2.32(3H, S), 2.77˜3.02(2H                                               , m), 3.49(4H, S), 6.69(1H,                                                   dt), 7.10˜7.67(3H, m),                                                  7.22(5H, S). molecular                                                        formula: C.sub.23 H.sub.25                                                    NO.HCl                             214                                                                               ##STR289##                             m.p. (°C.): 174 to 175                                                 elemental analysis as C.sub.23                                                H.sub.25 NO.sub.3 CHN calculate                                               d (%)69.086.553.50  found                                                     (%)69.126.413.43                   215                                                                               ##STR290##                             m.p. (°C.): 175 to 176                                                 elemental analysis as C.sub.30                                                H.sub.31 NO.sub.3 CHN calculate                                               d (%)79.446.893.09 found                                                      (%)79.046.872.77                   216                                                                               ##STR291##                             m.p. (°C.): 180 to 181                                                 elemental analysis as C.sub.26                                                H.sub.31 NO.sub.3.HCl CHN                                                     calculated (%)70.657.303.17                                                   found (%)70.347.053.07             217                                                                               ##STR292##                             m.p. (°C.): 228 to 230                                                 (dec.) elemental analysis as                                                  C.sub.23 H.sub.23 NO.sub.3.HCl                                                 calculated (%)69.436.083.52                                                  found (%)67.895.973.45                                                        1/2H.sub.2 O                                                                  (%)67.89 6.193.44                  218                                                                               ##STR293##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 2.48˜3.02(13H, m),                                                    3.48(2H, S), 6.73(1H, dt),                                                    7.10˜8.10(4H, m),                                                       7.22(5H, S). molecular                                                        formula: C.sub.23 H.sub.25                                                    NO.HCl                             219                                                                               ##STR294##                             m.p. (°C.): 211 to 213                                                 (dec.) elemental analysis as                                                  C.sub.24 H.sub.27 NO.HCl CHN                                                  calculated (%)75.477.393.67                                                   found (%)75.227.413.57             220                                                                               ##STR295##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.20˜2.60(7H, m),                                                     1.96(3H, d), 2.70˜2.97(2H                                               , m), 3.46(3H, S), 6.67(1H,                                                   dd), 7.21(5H,                                                                 S), 7.21˜7.61(5H, m).                                                   molecular formula: C.sub.22                                                   H.sub.25 NO.HCl                    221                                                                               ##STR296##                             m.p. (°C.): 170 to 171                                                 elemental analysis as C.sub.26                                                H.sub.31 NO.sub.3 CHN calculate                                               d (%)77.017.703.45 found                                                      (%)77.107.673.43                   222                                                                               ##STR297##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜2.40(13H, m),                                                    2.70˜3.00(2H, m),                                                       3.45(2H, S), 3.48(2H, S),                                                     3.86(3H, S), 3.91(3H, S),                                                     6.68(1H, tt), 6.80(1H, S),                                                    7.20(6H, S). molecular                                                        formula: C.sub.27 H.sub.33                                                    NO.sub.3.HCl                       223                                                                               ##STR298##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜2.40(15H, m),                                                    2.68˜3.00(2H, m),                                                       3.46(2H, S), 3.50(2H, S),                                                     3.88(3H, S), 3.93(3H, S),                                                     6.68(1H, tt), 6.83(1H, S),                                                    7.19(1H, S), 7.21(5H, S).                                                     molecular formula: C.sub.28                                                   H.sub.35 NO.sub.3.HCl              224                                                                               ##STR299##                             m.p. (°C.): 130 to 135                                                 elemental analysis as C.sub.26                                                H.sub.29 NO.sub.3.HCl CHN                                                     calculated (%)70.986.873.18                                                   found (%)70.816.723.10             225                                                                               ##STR300##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜3.50(16H, m),                                                    3.87(3H, S), 3.93(3H, S),                                                     6.80(1H, S), 7.00˜7.25                                                  (6H, m). molecular formula:                                                   C.sub.24 H.sub.29 NO.sub.3.HCl     226                                                                               ##STR301##                             m.p. (°C.): 186 to 188                                                 (dec.) .sup.1 H-NMR(CDCl.sub.3)                                               δ; 1.65˜2.10(7H,                                                  m), 2.65˜2.75(2H, m),                                                   3.25˜3.83(5H, m),                                                       3.92(3H, S), 3.98(3H, S),                                                     4.60(2H, S), 6.88(1H, S),                                                     7.19(1H, S), 7.26˜                                                      7.60(5H, m). molecular                                                        formula: C.sub.24 H.sub.29                                                    NO.sub.4                           227                                                                               ##STR302##                             m.p. (°C.): 220 to 221                                                 elemental analysis as C.sub.25                                                H.sub.31 NO.sub.3.HCl CHN                                                     calculated (%)69.837.503.26                                                   found (%)70.037.513.26             228                                                                               ##STR303##                             m.p. (°C.): 212 to 213                                                 elemental analysis as C.sub.25                                                H.sub.31 NO.sub.3.HCl CHN                                                     calculated (%)69.837.503.26                                                   found (%)69.627.383.15             229                                                                               ##STR304##                             m.p. (°C.): 229 to 230                                                 (dec.) elemental analysis as                                                  C.sub.25 H.sub.31 NO.sub.3.HCl                                                 calculated (%)69.837.503.26                                                  found (%)69.917.483.28             230                                                                               ##STR305##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.00˜3.50(14H, m),                                                    3.73(2H, S), 3.86(3H, S),                                                     3.93(3H, S), 6.82(1H, S),                                                     7.12(1H, S),                                                                  7.22˜7.80(4H, m).                                                       molecular formula: C.sub.24                                                   H.sub.28 N.sub.2 O.sub.5.HCl       231                                                                               ##STR306##                             m.p. (°C.): 210 to 211                                                 elemental analysis as C.sub.24                                                H.sub.28 N.sub.2 O.sub.5.HCl                                                  CH calculated (%)62.546.346.08                                                ound (%)62.486.345.96              232                                                                               ##STR307##                             m.p. (°C.): 234 to 236                                                 (dec.) elemental analysis as                                                  C.sub.24 H.sub.28 N.sub.2                                                     O.sub.5.HCl CHN calculated                                                    (%)62.546.346.08 found                                                        (%)62.56.255.83                    233                                                                               ##STR308##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 1.10˜3.43(14H, m),                                                    3.52(2H, S), 3.84(3H, S),                                                     3.91(3H, S), 6.35˜7.08                                                  (7H, m). molecular formula:                                                   C.sub.24 H.sub.29 NO.sub.4.HCl                                                N                                  234                                                                               ##STR309##                             m.p. (°C.): 146 to 148                                                 elemental analysis as C.sub.24                                                H.sub.29 NO.sub.4.HCl CHN                                                     calculated (%)66.517.293.53                                                   found (%)66.737.003.24             235                                                                               ##STR310##                             m.p. (°C.): 193 to 194                                                 elemental analysis as C.sub.25                                                H.sub.31 NO.sub.4.HCl CHN                                                     calculated (%)67.33 7.233.14                                                  found (%)67.437.223.13             236                                                                               ##STR311##                             m.p. (°C.): 226 to 228                                                 (dec.) elemental analysis as                                                  C.sub.25 H.sub.31 NO.sub.4.HCl                                                 calculated (%)67.337.233.14                                                  found (%)67.217.292.97             237                                                                               ##STR312##                             .sup.1 H-NMR(CDCl.sub.3)δ                                               ; 0.78˜3.40(14H, m),                                                    3.46(2H, S), 3.85(3H, S),                                                     3.91(3H, S), 5.01(2H, S),                                                     6.78(1H, S),                                                                  6.80˜7.43(9H, m),                                                       7.09(1H, S). molecular                                                        formula: C.sub.31 H.sub.35                                                    NO.sub.4.HCl                       238                                                                               ##STR313##                             m.p. (°C.): 224 to 226                                                 (dec.) elemental analysis as                                                  C.sub.23 H.sub.28 N.sub.2                                                     O.sub.3.2HCl CHN calculated                                                   (%)0.936.676.18 found                                                         (%)58.726.985.56 H.sub.2 O                                                    (%)58.606.845.94                   239                                                                               ##STR314##                             m.p. (°C.): 253 to 256                                                 (dec.) elemental analysis as                                                  C.sub.25 H.sub.31 NO.sub.3.HCl                                                 calculated (%)69.837.503.26                                                  found (%)69.607.493.27             240                                                                               ##STR315##                             m.p. (°C.): 225 to 226                                                 (dec.) elemental analysis as                                                  C.sub.24 H.sub.35 NO.sub.3.HCl                                                 calculated (%)68.318.603.32                                                  found (%)68.178.493.51             241                                                                               ##STR316##                             m.p. (°C.): 226 to 227                                                 (dec.) elemental analysis as                                                  C.sub.28 H.sub.31 NO.sub.3.HCl                                                 calculated (%)72.176.923.01                                                  found (%)71.717.072.85             242                                                                               ##STR317##                             m.p. (°C.): 243 to 245                                                 (dec.) elemental analysis as                                                  C.sub.28 H.sub.31 NO.sub.3.HCl                                                 calculated (%)72.176.923.01                                                  found (%)71.756.923.01             243                                                                               ##STR318##                             m.p. (°C.): 191 to 192                                                 elemental analysis as C.sub.26                                                H.sub.33 NO.sub.5.HCl CHN                                                     calculated (%)65.607.202.94                                                   found (%)65.347.272.79             244                                                                               ##STR319##                             m.p. (°C.): 219 to 221                                                 elemental analysis as C.sub.                                                  27 H.sub.35 NO.sub.6.HCl CHN                                                  calculated (%)64.097.172.77                                                   found (%)63.277.192.51                                                        1/2H.sub.2 O (%)62.967.242.72      245                                                                               ##STR320##                             .sup.1 H-NMR(D.sub.2 O)δ;                                                1.10˜3.12(14H, m),                                                     3.84(3H, S), 6.70(1H, S),                                                     6.84(1H, S). molecular                                                        formula: C.sub.16 H.sub.21                                                    NO.sub.3.HCl                       246                                                                               ##STR321##                             m.p. (°C.): 182 to 183                                                 elemental analysis as C.sub.30                                                H.sub.33 N.sub.5 O.sub.6 CHN                                                  calculated (%)64.395.9412.51                                                  found (%)64.425.7812.52            247                                                                               ##STR322##                             m.p (°C.): 240 to 241                                                  (dec.) elemental analysis as                                                  C.sub.26 H.sub.33 NO.sub.2                                                    S.sub.2.HCl CHN calculated                                                    (%)63.466.962.85 found                                                        (%)63.18.782.80                    248                                                                               ##STR323##                             m.p. (°C.): 180 to 185                                                 (dec.) elemental analysis as                                                  C.sub.23 H.sub.28 N.sub.2                                                     O.sub.3.2HCl CHN calculated                                                   (%)0.736.45 6.25 found                                                        (%)60.92.67 6.18                   249                                                                               ##STR324##                             m.p. (°C.): 230 to 232                                                 (dec.) elemental analysis as                                                  C.sub.35 H.sub.39 NO.sub.6.HCl                                                 calculated (%)69.356.652.31                                                  found (%)69.216.592.33             __________________________________________________________________________

The compounds obtained in Examples 178 to 249 were each examinedaccording to the above shown experimental test in view of the inhibitoryactivity. Results are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                        Inhibitory effect against acetylcholinesterase in vitro                                     Inhibitory                                                                    activity                                                                      on AChE                                                         Compound      IC.sub.50 (μM)                                               ______________________________________                                        178           >10                                                             179           5.4                                                             180           0.001                                                           181           0.094                                                           182           0.8                                                             183           5.3                                                             184           >5                                                              185           0.00082                                                         186           0.0015                                                          187           4.4                                                             188           0.081                                                           189           0.012                                                           190           0.02                                                            191           0.085                                                           192           0.013                                                           193           0.2                                                             194           0.069                                                           195           0.0071                                                          196           0.0013                                                          197           0.38                                                            198           0.0054                                                          199           0.023                                                           200           2.1                                                             201           15                                                              202           1.2                                                             203           0.009                                                           204           0.035                                                           205           0.014                                                           206           0.41                                                            207           0.049                                                           208           0.062                                                           209           0.43                                                            210           0.06                                                            211           2                                                               212           0.5                                                             213           0.05                                                            214           0.0084                                                          215           0.0042                                                          216           0.017                                                           217           0.14                                                            218           20                                                              219           19                                                              220           11                                                              221           0.033                                                           222           0.011                                                           223           0.0054                                                          224           0.003                                                           225           0.48                                                            226           0.0049                                                          227           0.01                                                            228           0.002                                                           229           0.04                                                            230           0.16                                                            231           0.004                                                           232           0.1                                                             233           0.046                                                           234           0.0018                                                          235           0.22                                                            236           3.6                                                             237           2.6                                                             238           0.072                                                           239           0.18                                                            240           0.0089                                                          241           0.22                                                            242           2.9                                                             243           4                                                               244           4.9                                                             245           5                                                               246           4.4                                                             247           --                                                              248           1.4                                                             249           0.62                                                            ______________________________________                                    

We claim:
 1. A cyclic amine compound having the following formula (XXV)or a pharmacologically acceptable salt thereof: ##STR325## in which J isa monovalent or divalent compound containing a phenyl group and selectedfrom the group consisting of (1) indanyl, (2) indanonyl, (3) indenyl,(4) indenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8)indanolyl and (9) indanonylidenyl, said phenyl group optionally beingsubstituted;B is --(CHR²²)_(r) --, --CO--(CHR²²)_(r) --, --NR⁴--(CHR²²)_(r) --, R⁴ being hydrogen, a lower alkyl, an acyl, a loweralkylsulfonyl, phenyl or benzyl, --CO--NR⁵ --(CHR²²)_(r) --, R⁵ beinghydrogen, a lower alkyl or phenyl, --CH═CH--(CHR²²)_(r) --,--OCOO--(CHR²²)_(r) --, --OOC--NH--(CHR²²)_(r) --, --NH--CO(CHR²²)_(r)--, --CH₂ --CO--NH--(CHR²²)_(r) --, --(CH₂)₂ --CO--NH--(CHR²²)_(r) --,--CH(OH)--(CHR²²)_(r) --, r being zero or an integer of 1 to 10, R²²being hydrogen or methyl, ═(CH--CH═CH)_(b) --, b being an integer of 1to 3, ═CH--(CH₂)_(c) --, c being zero or an integer of 1 to 9,═(CH--CH)_(d) ═, d being zero or an integer of 1 to 5; --CO--CH═CH--CH₂--, --CO--CH₂ CH(OH)--CH₂ --, --CH(CH₃)--CO--NH--CH₂ --,--CH═CH--CO--NH--(CH₂)₂ --, --NH--, --O--, --S--, adialkylaminoalkylcarbonyl or a lower alkoxycarbonyl; T is carbon; Q isnitrogen; and q is 2; K is hydrogen, phenyl, a substituted phenyl, anarylalkyl containing a phenyl group which may have a substituent,cinnamyl, a lower alkyl, pyridylmethyl, a cycloalkylalkyl,adamantanemethyl, furylmethyl, a cycloalkyl, a lower alkoxycarbonyl oran acyl group; and shows a single bond or a double bond, with theproviso that J is not indanonyl when B is --(CHR²²)_(r) --.
 2. A cyclicamine compound having the following formula (XXV) or a pharmacologicallyacceptable salt thereof: ##STR326## in which J is a monovalent ordivalent compound containing a phenyl group and selected from the groupconsisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl,(5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8) indanolyl, and(9) indanonylidenyl, said phenyl group optionally being substituted;B is--(CHR²²)_(r) --, r being zero or an integer of 1 to 10, R²² beinghydrogen or methyl, ═(CH--CH═CH)_(b) --, b being an integer of 1 to 3,═CH--(CH₂)_(c) --, c being zero or an integer of 1 to 9, ═(CH--CH)_(d)═, d being zero or an integer of 1 to 5; Q is nitrogen, T is carbon andq is 2; K is phenylalkyl or phenylalkyl which may have a substituent onthe phenyl group, cinnamyl, a lower alkyl, pyridylmethyl, acycloalkylalkyl, adamantanemethyl, furylmethyl, a cycloalkyl, a loweralkoxycarbonyl or an acyl group; and indicates a single bond or a doublebond, with the proviso that J is not indanonyl when B is --(CHR²²)_(r)--.
 3. A cyclic amine compound as claimed in claim 1 or apharmacologically acceptable salt thereof, in which J is (b) selectedfrom the group consisting of indanonyl, indenyl, indanedionyl andindanonylidenyl.
 4. A cyclic amine compound as claimed in claim 1 or apharmacologically acceptable salt thereof, in which B is --(CHR²²)_(r),═(CH--CH═CH)_(b), ═CH--(CH₂)_(c) or ═(CH--CH)_(d)═.
 5. A cyclic aminecompound as claimed in claim 1 or a pharmacologically acceptable saltthereof, in which J is indanonyl and B is ═(CH--CH═CH)_(b),═CH--(CH₂)_(c) -- or ═(CH--CH)_(d) ═.
 6. A cyclic amine compound asclaimed in claim 1 or a pharmacologically acceptable salt thereof, whichis selected from the group consistingof:1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-ylidenyl)methylpiperidine,1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine,1-benzyl-4-((5,6-dimethoxy-1-oxoindanon)-2-yl)-propenylpiperidine.
 7. Atherapeutical composition which comprises a pharmacologically effectiveamount of the cyclic amine compound as defined in claim 1 or apharmacologically acceptable salt thereof and a pharmacologicallyacceptable carrier.
 8. A method for treating a disease accompanied byacetylcholinesterase activity by administering to a human patient aneffective amount of the cyclic amine compound as defined in claim 1 or apharmacologically acceptable salt thereof for inhibiting theacetylcholinesterase activity.
 9. A method as claimed in claim 7, inwhich the disease is senile dementia.
 10. A method as claimed in claim7, in which the disease is senile dementia of the Alzheimer type.
 11. Acompound having the formula ##STR327## in which J is selected from thegroup consisting of ##STR328## in which t is an integer of 1 to 4 and Sis selected from the group consisting of hydrogen, alkyl having 1 to 6carbon atoms, alkoxy having 1 to 6 carbon atoms, and, when t is 2,(S)_(t) can be methylenedioxy or ethylenedioxy connected to two adjacentcarbon atoms on the phenyl ring, B is selected from the group consistingof --(CHR²²)_(r) --, --CH═CH--(CHR²²)_(r) --, ═(CH--CH═CH)_(b),═CH--(CH₂)_(c) -- and ═(CH--CH)_(d) ═, R²² is hydrogen or methyl, r iszero or an integer of 1 to 10, b is an integer of 1 to 3, c is zero oran integer of 1 to 9 and d is zero or an integer of 1 to 5:K ishydrogen, phenyl, substituted phenyl, phenylalkyl, phenylalkyl having asubstituent on the phenyl ring, cinnamyl, lower alkyl, pyridylmethyl,cycloalkylalkyl, adamantanemethyl, furylmethyl, cycloalkyl,alkoxycarbonyl or acyl; and indicates a single bond or a double bond,with the proviso that J is not ##STR329## when B is --(CHR²²)_(r) --, ora pharmacologically acceptable salt thereof.
 12. A compound having theformula ##STR330## wherein c is zero or an integer of 1 to 9, S ishydrogen or a substituent on the phenyl ring, and t is an integer of 1to 4, with the proviso that (S)_(t) can be a methylenedioxy group or anethylenedioxy group joined to two adjacent carbon atoms of the phenylring; andK is hydrogen, phenyl, substituted phenyl, phenylalkyl,phenylalkyl having a substituent on the phenyl ring, cinnamyl, loweralkyl, pyridylmethyl, cycloalkylalkyl, adamantanemethyl, furylmethyl,cycloalkyl, alkoxycarbonyl or acyl, or a pharmacologically acceptablesalt thereof.
 13. A compound having the formula ##STR331## wherein t isan integer of 1 to 4, and S is selected from the group consisting ofhydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbonatoms, and, when t is 2, (S)_(t) can be methylenedioxy or ethylenedioxyconnected to two adjacent carbon atoms on the phenyl ring, or apharmacologically acceptable salt thereof.
 14. A compound having theformula ##STR332## wherein J is ##STR333## t is an integer of 1 to 4 andS is selected from the group consisting of hydrogen, alkyl having 1 to 6carbon atoms, alkoxy having 1 to 6 carbon atoms, and, when t is 2,(S)_(t) can be methylenedioxy or ethylenedioxy connected to two adjacentcarbon atoms on the phenyl ring;when J is ##STR334## B is--CH═CH--(CHR²²)_(r) 13 wherein r is zero or an integer of 1 to 10 andR²² is hydrogen or methyl, and when J is ##STR335## B is selected fromthe group consisting of ═(CH--CH═CH)_(b) -- wherein b is an integer of 1to 3, ═CH--(CH₂)_(c) -- wherein c is zero or an integer of 1 to 9 or═(CH--CH)_(d) -- wherein d is zero or an integer of 1 to 5; and K isselected from the group consisting of phenyl, substituted phenyl,arylalkyl, ring-substituted arylalkyl, alkylcycloalkyl, cinnamyl,benzoyl and ring-substituted benzoyl, indicates a single or double bond,or a pharmacologically acceptable salt thereof.
 15. A compound asclaimed in claim 14 in which K is benzyl.
 16. A compound as claimed inclaim 15 in which B is ═CH--(CH₂)_(c) and J is ##STR336##
 17. A compoundas claimed in claim 14, which is1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]-methylpiperidine orpharmacologically acceptable salt thereof.